Functional powders for oral delivery

ABSTRACT

In certain embodiments the invention is directed to a drug formulation for gastrointestinal deposition comprising a non-compressed free flowing plurality of particles comprising a core comprising a drug and a pharmaceutically acceptable excipient, said core overcoated with a functional coating, said drug particles having a mean diameter of greater than 10 μm to about 1 mm.

This application claims the benefit of U.S. Provisional Ser. No.60/317,522, filed Sep. 5, 2001, the entire disclosure of which is herebyincorporated by reference.

FIELD OF THE INVENTION

The present is directed to a functional powders for oral use.Preferably, the powders are used in a multiple dose delivery devicewhich dispenses a unit dose of the powder upon actuation.

BACKGROUND OF THE INVENTION

The most prominent mode of delivery of therapeutic agents is by the oralroute by means of solid dosage forms such as tablets and capsules. Oraladministration of solid dosage forms is more convenient and acceptedthan other modes of administration, e.g. parenteral administration.However, the manufacture, dispensing and administration of solid dosageforms are not without associated problems and drawbacks.

With the manufacture of solid dosage forms, in addition to the activeagent, it is necessary to combine other ingredients in the formulationsfor various reasons, such as to enhance physical appearance, to providenecessary bulk for tableting or capsuling, to improve stability, toimprove compressibility or to aid in disintegration afteradministration. However, these added excipients have been shown toadversely influence the release, stability and bioavailability of theactive ingredient. The added excipients are a particular problem withdrugs which require a high dose in order to provide a therapeuticeffect, e.g., biphosphonate drugs. The inclusion of the additionalexcipient can make the final tablet extremely large which could resultin esophogeal damage due to the physical characteristics of the dosageform if it is not swallowed properly. Esophogeal damage can also becaused by toxicity caused by the drug itself, if the tablet becomeslodged in the throat or has an increased transit time through theesophagus, due to its increased size.

Further, the tableting of certain drugs has many associated productionproblems. In particular, many drugs, e.g., acetaminophen, have poorcompressibility and cannot be directly compressed into solid dosageforms. Consequently, such drugs must either be wet granulated ormanufactured in a special grade in order to be tableted which increasesmanufacturing steps and production costs.

The adherence to good manufacturing practices and process controls isessential in order to minimize dosage form to dosage form and batch tobatch variations of the final product. Even strict adherence to thesepractices still is not a guarantee that acceptable variation will occur.

With the high cost of industrial scale production and governmentalapproval of solid dosage forms, such formulations are often available ina limited number of strengths, which only meet the needs of the largestsectors of the population. Unfortunately, this practice leaves manypatients without acceptable means of treatment and physicians in aquandary with respect to individualizing dosages to meet the clinicalneeds of their patients.

The dispensing of oral solid dosage forms also makes the formulationssusceptible to degradation and contamination due to repackaging,improper storage and manual handling.

There are also many patients who are unable or unwilling to takeconventional orally administered dosage forms. For some patients, theperception of unacceptable taste or mouth feel of a dose of medicineleads to a gag reflex action that makes swallowing difficult orimpossible. Other patients, e.g., pediatric and geriatric patients, findit difficult to ingest typical solid oral dosage forms, e.g., due totablet size.

Other patients, particularly elderly patients, have conditions such asachlorhydria which hinders the successful use of oral solid dosageforms. Achlorhydria is a condition wherein there is an abnormaldeficiency or absence of free hydrochloric acid in the gastricsecretions of the stomach. This condition hinders the disintegrationand/or dissolution of oral solid dosage forms, particularly dosage formswith high or insoluble excipient payloads. Thus, as the present dosageform is in multiparticulate form, it does need to undergo disintegrationand/or dissolution to the same extent as solid dosage forms.

Flavored solutions/suspensions of some therapeutic agents have beendeveloped to facilitate the oral administration of oral agents topatients normally having difficulty ingesting conventional solid oraldosage forms. While liquid formulations are more easily administered tothe problem patient, liquid/suspension formulations are not withouttheir own significant problems and restrictions. The liquid dose amountis not as easily controlled compared with tablet and capsule forms andmany therapeutic agents are not sufficiently stable insolution/suspension form. Indeed, most suspension type formulations aretypically reconstituted by the pharmacist and then have a limited shelflife even under refrigerated conditions. Another problem with liquidformulations which is not as much a factor with tablets and capsules isthe taste of the active agent. The taste of some therapeutic agents isso unacceptable that liquid formulations are not a viable option.Further, solution/suspension type formulations are typically notacceptable where the active agent must be provided with a protectivecoating, e.g. a taste masking coating or an enteric coating to protectthe active agent from the strongly acidic conditions of the stomach.

Due to the disadvantages of known drug delivery discussed above (as wellas other disadvantages) there exists a need in the art for thedevelopment of a multiparticulate formulation for facilitating deliveryof a wide range of therapeutic agents for gastrointestinal depositionand which minimize pulmonary deposition of materials having undesirableor unknown pulmonary toxicology but which are approved for oraldelivery. In preferred embodiments, the formulation contains minimalexcipient and is used in a multiple dose delivery device which dispensesa unit dose of the powder upon actuation.

OBJECTS OF THE INVENTION

It is an object of the invention to provide a multiparticulateformulation containing a therapeutic agent for gastrointestinaldeposition.

It is an object of certain embodiments of the invention to provide amultiparticulate formulation having at single coating which aids in thefunctionality of the formulation.

It is an object of certain embodiments of the invention to provide amultiparticulate formulation having at least two coatings which aid inthe functionality of the formulation.

It is an object of certain embodiments of the invention to provide ahigh load multiparticulate formulation with minimal use of excipient.

It is a further object of certain embodiments of the invention toprovide a multiparticulate formulation with improved weight variability,from dose to dose and batch to batch.

It is a further object of certain embodiments of the invention toprovide a multiparticulate formulation which has minimal change incohesiveness in response to humidity change

It is a further object of certain embodiments of the invention toprovide a multiparticulate formulation which has minimal potential forwater coalescence on the surface of the particles.

It is a further object of certain embodiments of the invention toprovide a multiparticulate formulation which has minimal static chargebetween the particles.

It is an object of certain embodiments of the invention to provide acoated multiparticulate formulation which provides a controlled ordelayed release of the active agent contained therein.

It is an object of certain embodiments of the invention to provide acoated multiparticulate formulation which tastemasks the active agenttherein.

It is an object of certain embodiments of the invention to provide acoated multiparticulate formulation which contains a salivary stimulantto facilitate the swallowing of a unit dose of the multiparticulatesupon oral delivery.

It is an object of the certain embodiments of invention to provide acoated multiparticulate formulation which contains a texture modifier toimprove mouthfeel upon oral delivery.

It is an object of certain embodiments of the invention to provide acoated multiparticulate formulation which has a desired particle rangein order to minimize pulmonary aspiration of particles.

It is an object of certain embodiments of the invention to provide acoated multiparticulate formulation which has a desired particle rangein order to improve functionality of a the formulation in a multipleunit dosing device which delivers a unit dose of the formulation fororal administration or delivery upon actuation.

It is an object of certain embodiments of the invention to provide acoated multiparticulate formulation which has improved performance whenused in a multiple unit dosing device which delivers a unit dose of theformulation for oral administration or delivery upon actuation.

It is an object of certain embodiments of the invention to provide acoated multiparticulate formulation which when divided into unit doses(e.g. with the use of a multiple unit dosing device) has weightuniformity of the formulation which is within the acceptable range ofthe weight uniformity of equivalent dosage forms which are tablets orcapsules. A detailed discussion of weight uniformity is found in theUSP/NF 23/18 section 905, hereby incorporated by reference in itsentirety for all purposes.

It is an object of certain embodiments of the invention to providemethods of preparation of the coated multiparticulate dosage formdisclosed herein.

It is an object of certain embodiments of the invention to providemethods of preparation of the multiple unit delivery systems containingthe coated multiparticulate dosage form disclosed herein.

It is an object of certain embodiments of the invention to providemethods of preparation of multiparticulate dosage forms having a desiredparticles range.

It is an object of certain embodiments of the invention to providemethods of administering an active agent comprising administering acoated multiparticulate dosage form disclosed herein.

It is an object of certain embodiments of the invention to providemethods of administering an active agent comprising administering acoated multiparticulate dosage form disclosed herein via the use of amultiple unit delivery systems.

The above objects of the invention, and others are achieved by virtue ofthe present invention, which in certain embodiments is directed to adrug formulation for gastrointestinal deposition comprising anon-compressed free flowing plurality of particles comprising a corecomprising a drug, the core overcoated with a functional coating.

In certain embodiments, the invention is directed to a drug formulationfor gastrointestinal deposition comprising a non-compressed free flowingplurality of particles comprising a core comprising a drug and apharmaceutically acceptable excipient, said core overcoated with afunctional coating.

In certain embodiments, the invention is directed to a drug deliverysystem for delivery of a drug for gastrointestinal deposition. Thesystem comprises a multiple unit dosing device comprising a housing andan actuator, the device containing multiple doses of themultiparticulate formulation disclosed herein, the device upon actuationdelivering a unit dose of the multiparticulates for gastrointestinaldeposition, the multiparticulates having a mean particle size of greaterthan 10 μm and preferably less than about 1 mm in order to minimizepulmonary deposition of the multiparticulates and such that an effectivedose of the drug cannot be delivered into the lower lung of a humanpatient. The drug delivery system can be used to administer the unitdose of multiparticulates into the oral cavity of the patient (in-vivo)or to dispense the unit dose into an intermediate receptacle (ex-vivo)for subsequent gastrointestinal deposition. Oral drug delivery systemsand devices for oral powders are disclosed in PCT/IB01/00251, herebyincorporated by reference in its entirety for all purposes.

In certain embodiments, the invention provides a method of preparing adrug delivery system for delivering multiple doses of a drug forgastrointestinal deposition comprising preparing a multiparticulate drugformulation as disclosed herein in a manner wherein the drug particleswhen placed in the oral cavity and swallowed are deposited to thegastrointestinal tract and not deposited in any substantial amount tothe lungs; and placing multiple unit doses of said drug formulation in adevice which meters a single unit dose for delivery.

In certain embodiments, the invention provides a method of treating apatient in need of multiple doses of a drug for gastrointestinaldeposition comprising preparing multiparticulates comprising drugparticles as disclosed herein in a manner wherein the drug particleswhen placed in the oral cavity and swallowed are deposited to thegastrointestinal tract and not deposited in any substantial amount tothe lungs; placing multiple unit doses of the multiparticulates in adevice which meters a single unit dose for delivery; and either (a)administering the unit dose into the oral cavity of a patient or (b)dispensing the unit dose into an intermediate receptacle and thereafteradministering the unit dose into the oral cavity of the patient.

In certain embodiments, the invention provides a drug formulation forgastrointestinal deposition comprising a non-compressed free flowingplurality of particles comprising a drug and a pharmaceuticallyacceptable excipient, the particles having a mean diameter of greaterthan 10 μm to about 1 mm.

In certain embodiments, the particles of the invention comprise at leastabout 40% drug; at least about 50% drug; at least about 60% drug; atleast about 80% drug; or at least about 90% drug.

In certain embodiments, the invention provides a method for delivery ofa drug comprising delivering the multiparticulates disclosed hereincomprising drug particles via the use of a multiple unit dosing devicecomprising a housing and an actuator, the device upon actuationdelivering a unit dose of the multiparticulates disclosed herein, andthereafter re-using said device to deliver additional unit doses of themultiparticulates at appropriate dosing intervals.

In certain embodiments of the invention, greater than about 80% of theunit dose is deposited in the gastrointestinal tract, preferably greaterthan about 90% or greater than about 95%, or greater than about 99% andmost preferably, about 100% of the unit dose is deposited in thegastrointestinal tract.

In preferred embodiments of the invention, the unit dose comprises adiscreet collection of multiparticulates. For purposes of the invention,a “discreet collection” means that the multiparticulates are in the formof a non-compressed free flowing unit and not dispersed in a cloud ormist, which effectively minimizes inhalation of the active agent intothe lungs of the patient. The unit dose can be, e.g., from about 0.01 mgto about 1.5 g, depending on the dose of the active agent beingdelivered. For example, the unit dose can be from about 1 mg to about100 mg or from about 10 mg to about 50 mg. Preferably, the unit dose isadministered to the tongue, most preferably towards the front of thetongue behind the teeth, where it can be easily swallowed with orwithout the need for an additional fluid. However the invention doescontemplate delivery to any portion of the tongue, taking into account,e.g., the taste sensations of different sections of the tongue and/orindividual patient preference associated with comfort, e.g. mouthposition.

In certain embodiments of the invention, the mean diameter of the drugparticles is of a size which minimizes their capacity to be inhaled intothe lower lung. Typically, the mean particle size of the drug particles(or agglomerates) is greater than 10 μm, preferably greater than about50 μm or greater than about 75 μm. In certain embodiments of theinvention, the mean particle size range of the drug particles is fromabout 100 μm to about 1 mm, preferably from about 50 μm to about 500 μm.In preferred embodiments, greater than 80% of the drug particles havethe above disclosed diameter (not mean diameter), e.g. 80% of the drugparticles have a diameter of greater than 10 μm, or a diameter of fromabout 100 μm to about 1 mm. In other embodiments, greater than about 90%of the drug particles have the above disclosed diameter.

In certain embodiments of the invention, the mean diameter of the drugparticles does not vary by greater than about 20%, preferably notgreater than about 15% and most preferably not greater than about 10%.

In certain embodiments of the invention, the multiparticulates comprisea pharmaceutically acceptable excipient. The excipient preferably doesnot comprise more than about 60% by weight of the formulation; morepreferably not more than about 50%; more preferably not more than about40% by weight by weight; more preferably not more than about 20% byweight multiparticulates by weight, and most preferably not more thanabout 10% by weight of the formulation.

In certain embodiments of the invention, the multiple doses of the drugformulation disclosed herein are contained in a reservoir. The reservoircan contain an amount of multiparticulates to provide any number of unitdoses, e.g. from about 2 doses to about 400 doses. For ease in patientcompliance, the reservoir has a sufficient quantity of to provide e.g. adays supply, a months supply or a years supply of doses, e.g. 30 or 365for once daily dosing for a month or year, respectively.

In order to aid in patient compliance, certain embodiments of theinvention include a counter or indicator to display the number of dosesremaining in the system or the number of doses actuated.

In certain embodiments of the invention, the unit doses are individuallymetered prior to actuation, e.g., in the form of capsules or blisters,wherein each blister contains one individual unit dose. The system canbe capable of containing any multiple of pre-metered unit doses, e.g.from about 2 to about 400 blisters.

The invention is also directed to methods of delivery (e.g., in vivoadministration and ex vivo dispensing) and methods of treatmentutilizing any of the disclosed embodiments directed to compositions ofmatter. The invention is also directed to methods of preparation of allof the disclosed embodiments.

The invention is also directed to methods of providing a therapeuticeffect to a patient comprising administering to the patient a unit doseof a drug utilizing the systems and formulations disclosed herein. Theinvention is also directed to methods of preparing the systems anddevices.

For purposes of the present invention, the term “device” refers to anapparatus capable of delivering a unit dose of drug.

The term “system” refers to a drug delivery device in combination withthe disclosed multiparticulate drug having the specifications disclosedherein, e.g. drug particle size, excipient type, etc.

The term “discreet collection” refers to a non-compressed free flowingunit of multiparticulates with minimal particulate matter beingdispersed in the surrounding environment (e.g., as a cloud or mist).

The term “drug” refers to any agent which is capable of providing atherapeutic effect to a patient upon gastrointestinal deposition. Thisencompasses all drugs which are intended for absorption for a systemiceffect (regardless of their actual bioavailability) as well as drugsintended for a local effect in the gut and/or oral cavity, e.g.nystatin, antibiotics or local anesthetics.

The term “particle size” refers to the diameter of the particle.

The term “deposition” means the deposit of the unit dose at the intendedpoint of absorption and/or action. For example, gastro-intestinaldeposition means the intended deposit of the unit dose in thegastrointestinal system for e.g., absorption for a systemic effect or toexert a local effect. Pulmonary deposition means the intended deposit ofdrug into the lungs in order to provide a pharmaceutical effect,regardless that the unit dose may enter the oral cavity prior topulmonary deposition.

The term “dispense”, when used in connection with the devices andsystems of the present invention, means that the device or systemdelivers the unit dose ex vivo with the intent of subsequentadministration to a mammal. For example, the device or system candispense the unit dose into a food, a liquid, a spoon, or anotherintermediate receptacle.

The term “administer”, when used in connection with the devices andsystems of the present invention, means that the device or systemdelivers the unit dose in vivo, i.e., directly into the gastrointestinaltract of a mammal.

The term “deliver” is meant to cover all ex vivo and in vivo delivery,i.e., dispensing and administering, respectively.

The term “patient” refers to humans as well as other mammals in need ofa therapeutic agent, e.g., household pets or livestock. This term alsorefers to humans or mammals in need of or receiving prophylactictreatment.

The term “functional coat” means a coating on a drug particle whichprovides a controlled release of the drug (e.g., a sustained release), adelayed release of the drug (e.g., via an enteric coating), tastemasking, salivary stimulation, a moisture barrier, texture modification,minimization of surface asperities, chip resistance, pliability or anycombination of any of the foregoing.

In certain embodiments, the particulates are defined fuctionally withrespect to the fact that they are of a size such that an effective dosecannot be delivered into the lower lung of a human patient. However,this definition should be understood to mean that a small percentage ofdrug (but not an amount effective to render a therapeutic effect) may infact be inadvertently delivered to the lungs of the patient. Also, thisdefinition is meant to define the particles, but not to limit the use ofthe invention to the treatments of humans only. The invention may beused for delivering doses of drugs to other mammals as well.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of adhesion vs. humidity for standard powders.

FIG. 2 is a graph of adhesion vs. humidity for powders of the presentinvention.

FIG. 3 is a dissolution profile of Indomethacin & 4% PVP K-30 wetgranulation in a pH 6.8 phosphate buffer made in accordance with anembodiment of the present invention.

FIG. 4 is a pH 6.8 phosphate buffer dissolution profile of Indomethacin& 10% PEG6000 melt granulation made in accordance with an embodiment ofthe present invention.

FIG. 5 is a 0.1 N Hydrochloric Acid dissolution profile of Indomethacin& 10% PEG6000 & 15% Acryl-eze melt granulation made in accordance withan embodiment of the present invention.

FIG. 6 is a pH 6.8 phosphate buffer dissolution profile of Indomethacin& 10% PEG6000 & 15% Acryl-eze melt granulation made in accordance withan embodiment of the present invention.

FIG. 7 is a 0.1 N Hydrochloric Acid dissolution profile of Indomethacin& 15% Sureteric & 10% PEG6000 melt granulation made in accordance withan embodiment of the present invention.

FIG. 8 is a 6.8 pH phosphate buffer dissolution profile of Indomethacin& 15% Sureteric & 10% PEG6000 melt granulation made in accordance withan embodiment of the present invention.

FIG. 9 is a 0.1 N Hydrochloric Acid dissolution profile of Indomethacin& 15% Sureteric melt granulation made in accordance with an embodimentof the present invention.

FIG. 10 is a 6.8 pH phosphate buffer dissolution profile of Indomethacin& 15% Sureteric melt granulation made in accordance with an embodimentof the present invention.

FIG. 11 is a 0.1 N Hydrochloric Acid dissolution profile of Indomethacin& 15% Sureteric & 10% Lustre Clear melt granulation made in accordancewith an embodiment of the present invention.

FIG. 12 is a 6.8 pH phosphate buffer dissolution profile of Indomethacin& 15% Sureteric & 10% Lustre Clear melt granulation made in accordancewith an embodiment of the present invention.

FIG. 13 depicts the particle size distribution for the formulations madein accordance with an embodiment of the present invention.

DETAILED DESCRIPTION

In general, it has been recognized in the art that dry powder inhalationor insufflation formulations must consist of particles of a size ofabout 2 microns in diameter in order for the particles, when inhaled, toreach the peripheral or “deep” lung, including alveoli. Particles largerthan 10 microns in diameter are not able to reach the deep lung wheninhaled because they are collected on the back of the throat and upperairways in humans. Therefore, known powder delivery systems have beenformulated with particle sizes of less than 10 microns in order for theparticles to reach the intended site of action, the pulmonary system.Known powder delivery devices have not contemplated delivery ofparticles from a multi-dose delivery device to achieve gastrointestinaldeposition, and therefore have avoided the use of drug particles havinga large size, e.g. greater than 10 microns. By virtue of the inventiondisclosed in Applicants copending application, PCT/IB01/00251, it hasbeen a surprising discovery that drug particles greater than 10 micronscan be delivered from a multi-use drug delivery device forgastrointestinal deposition in a patient in order to minimize theinhalation of the drug particles into the lungs, in order to havesubstantially all of the dose deposited in the gastrointestinal system.By virtue of the present invention, it has been surprisingly discoveredthat powders that can be used in such devices can be functionally coatedin order to provide desired characteristics with respect to their use inthe device, e.g., increased flowability and decreased bridging(disclosed in more detail below) as well as characteristics of thepowder itself, e.g. an acceptable weight variability. The powders can beused in the device or can be administered without the use of the device,e.g., by using a sachet.

In preferred embodiments, the drug formulation for gastrointestinaldeposition of the invention comprising a non-compressed free flowingplurality of particles comprising a core comprising a drug and apharmaceutically acceptable excipient, with the core overcoated with afunctional coating.

In preferred embodiments, the core of the invention comprises drugcoated with the excipient and a functional coat overcoating theexcipient coat, thus providing a dual coated powder. The dual coatedpowder has improved functionality as a multiparticulate dosage form.

In other preferred embodiments, the core of the invention comprises druginterdispersed with the excipient and a functional coat overcoating thecore. In these embodiments, the core can be prepared by wet granulationor by melt granulation. It has been surprisingly found that preparingthe core by wet granulation or melt granulation results in a decreasedfraction of fine particles in the resultant dosage form.

Depending on the choice of the initial excipient overcoat, single coatedparticles can have a surface area which is not smooth, with asignificant degree of rugosity and surface asperities. Such particleshave significant associated problems which decrease the usefulness andbenefits of multiparticulate dosage forms.

For example, the presence of surface asperities on the surface of theparticles provides gaps and cavernous areas which promote thecoalescence of water onto the surface of the particles. The accumulationof water onto the surface of the particles promoted cohesiveness of theparticles which is undesirous in the multiparticulate dosage form of thepresent invention, e.g., due to decreased flowability. Accordingly, theuse of the present invention may not be able to be used to full benefitin areas which have increased humidity. This is relevant not only by thegeographic location of use, e.g., a tropical area, but also relevant bythe workplace, e.g. air conditioned buildings which may result inincreased humidity. The functional overcoat can be provided in order toprovide a relatively smooth surface area with minimal rugosity andsurface asperities. The overcoated particles can then be resistant tothe deleterious effects of moisture and humidity of the functionality ofthe multiparticulate dosage form. The moisture resistant overcoat mayhave the added benefit of protecting the stability of the drug containedtherein.

Another functional problem associated with particles with increasedrugosity and surface asperities is the presence of points or protrusionswhich rise from the surface of the particle and increase cohesiveness bymultiple pathways.

One reason for increased adhesion between particles due to surfacepoints or protrusions is due to physical interlocking between adjacentparticles in the formulation. The protrusions of one particles caninterlock between a “valley” in another particle. Alternatively,protrusions can actually interlock due to “jigsaw” type characteristicsof the protrusions. The resultant is agglomeration of particles anddecreased flowability of the formulation. An overcoat which smooths thesurface can minimize asperities and rugosity and increase thefunctionality of the formulation.

Another reason for increased adhesion between particles due to surfacepoints or protrusions is due to the fact that charge tends to gather atthese points and protrusions. Thus, the existence of localized chargecan increase electrostatic forces between the particles and promoteagglomeration and adhesion. An overcoat which smooths the surface of theunderlying particle and decreases asperities and rugosity can decreaseaccumulation and adhesion due to electrostatic forces. Electrostaticforces can also be minimized by coating a substrate with a conductivepolymer, disclosed in more detail below.

The concept of rugosity of particles can be quantified by a rugosityindex. The calculation of the rugosity index involves the concept of a“convex hull”. A convex hull is a minimum enveloping boundary fitted toan outline of the measured particle that is nowhere concave. Therugosity index is defined as the perimeter of the particles outlinedivided by the perimeter of the convex hull. According to this index,certain embodiments of the multiparticulates of the present inventioncan have a mean rugosity index of between 1.0 and 1.5, more preferablyfrom about 1.0 to about 1.2. In other embodiments, greater than 80% ofthe particles of the invention have a rugosity index within thedisclosed mean range. In other embodiments, greater than 90% of theparticles of the invention have a rugosity index within the disclosedmean range.

Another calculation index which can be used in the present invention isa roundness index. When the particles of the present invention arecoated as disclosed herein, certain embodiments will exhibit a roundnessof the particles. The roundness index can be calculated as the square ofthe perimeter of the particles outline divided by 4π (cross-sectional orprojection area of particle outline). According to this index, certainembodiments of the multiparticulates of the present invention can have amean roundness index of between 0.70 and 1.0, more preferably from about0.85 to about 1.0. In other embodiments, greater than 80% of theparticles of the invention have a roundness index within the disclosedmean range. In other embodiments, greater than 90% of the particles ofthe invention have a roundness index within the disclosed mean range.

In certain embodiments of the invention, flowability is improved byvirtue of the functional coatings, without the need for certain flowaids known in the art such as the inclusion of silicone dioxide. The useof silicone dioxide is not preferred in the present invention becausethis compound is not suited for inhalation, should a patientaccidentally or inadvertently have aspiration into the lungs of afraction of the unit dose.

Adhesion and agglomeration also leads to the concept of bridging whichis particularly problematic with respect to the use of themultiparticulate formulation disclosed herein in multiple unit dosingdevices. When multiple unit doses of the multiparticulates of thepresent invention are stored in containers, e.g., reservoirs, andunloaded therefrom through an opening or openings in the bottom of thecontainer, the containers are often designed to have very steep wallsadjacent the opening to aid the outward flow of the multiparticulates.Nevertheless the multiparticulates can become clogged and will havereduced or no flow out of the container. This phenomenon is generallytermed “bridging” since the bulk material tends to assume a curved orcupola-like shape. It is known that sometimes vibrating or knocking thecontainer walls from outside is sufficient to break the integrity of thebridge enable the flow to return to normal. Sometimes, however, suchvibrating or knocking results in container wall vibrations which furthercompact the material resulting in an even more rigid and indestructiblebridge being formed, or the shaking and vibrating of the container canbreak or damage the dosing device.

One aspect of the present invention is formulating the mean particlessize of the particulates to have a diameter which can minimize orpossibly eliminate bridging when the formulation is included in a systemin a multiple unit dosing device (e.g., a hopper base device). Themultiple unit dosing devices as disclosed herein and in PCT/IB01/00251may be susceptible to bridging which could result in reduced flow andinaccurate dosing. It has been discovered that bridging can besignificantly reduced if the particles size of the multiparticulates areno greater than {fraction (1/14)}th or {fraction (1/15)}th the diameterof the exit opening in the reservoir or container of the bulkformulation. The typical opening of a multiple unit dosing device isabout 7 mm, thus, a preferred particle size of the present invention isa mean particles size of less than about 500 micrometers. If the meanparticle size of the multiparticulates are significantly greater than{fraction (1/14)}th the size of the diameter of the exit opening, theresultant bridging and reduced flow will increase. For example, bridgingmay be more problematic if the mean particle size of the formulation is1.5 mm in a dosing device with a 7 mm exit. Bridging is also increasedif the particulates have asperities and protrusions due to interlockingas discussed above. With interlocking, the particles cannot moverelative to each other in the direction of an applied driving forcecomponent, such as gravity, due to the presence of a force such as africtional force component which is larger than the driving forcecomponent and normal thereto and which urges the particles against eachother. The frictional force component that holds the particles togetheris proportional to the coefficient of friction of the particular bulkmaterial. Thus, materials having relatively large coefficients offriction have a relatively large tendency to bridge. The inclusion of acoating or overcoating which smooths the surface of themultiparticulates will result in decreased bridging due to decreasedinterlocking.

The multiparticulates of the present formulation, when in motion areknown to have a relatively smaller coefficient of friction than at rest.The present invention is therefore directed to devices which reduce thecoefficient of friction between multiparticulates by producing relativemotion therebetween in order to reduce bridging effects. This can beaccomplished, for example, by the inclusion of a internal rake or leverwhich agitates and moves the particles within the device upon actuation,or by a vibrating mechanism which is preferably activated uponactuation.

The present invention is therefore directed to particles having a novelsize range, which are dependent on a number of factors. In order toreduce pulmonary inhalation, the mean diameter of the particles arepreferably greater than about 10 micrometers and preferably greater thanabout 50 micrometers and the mean diameter of the multiparticulates arepreferably less than about 500 micrometers as a typical dosing devicewill have an exit opening of about 7 mm. However, this range is notmeant to be limiting as the dosing devices (e.g., hopper base devices)can have different size openings and the formulations of the presentinvention may be used without the device.

As bridging and aspiration will depend on the actual size of theparticles in proximity to each other, mean particles size is only onefactor to consider, as the actual particles in proximity to each othermay wind up being very large or very small, despite the mean particlessize of the entire batch.

Accordingly, with respect to aspiration, it is preferred that greaterthan 90% of said particles have a diameter of greater than about 10 μm.Preferably, greater than 95% of said particles have a diameter of greatthan about 10 μm. More preferably, greater than 99% of said particleshave a diameter of greater than about 10 μm.

In other embodiments, greater than 90% of said particles have a diameterof greater than about 50 μm. Preferably, greater than 95% of saidparticles have a diameter of great than about 50 μm. More preferably,greater than 99% of said particles have a diameter of greater than about50 μm.

In other embodiments, greater than 90% of said particles have a diameterof less than about 500 μm. Preferably, greater than 95% of saidparticles have a diameter of less than about 500 μm. More preferably,greater than 99% of said particles have a diameter of greater than about500 μm.

In other embodiments, greater than 90% of said particles have a diameterof greater than about 50 μm and greater than 90% of said particles havea diameter of less than about 500 μm. Preferably, greater than 95% ofsaid particles have a diameter of great than about 50 μm and greaterthan 95% of said particles have a diameter of less than about 500 μm.More preferably, greater than 99% of said particles have a diameter ofgreater than about 50 μm and greater than 99% of said particles have adiameter of greater than about 500 μm.

In order to achieve the desired lower limit of the particles size of thepresent invention the invention, in certain embodiments is directed to amethod of preparation comprising air jet sieving particles to removefine particles. In particular embodiments, the invention is directed toa method of preparing a multiparticulate drug formulation forgastrointestinal deposition comprising preparing a non-compressed freeflowing plurality of particles comprising a core comprising a drug and apharmaceutically acceptable excipient as disclosed herein and air jetsieving the particles to separate the cores from fine particles; andthereafter overcoating said core with a functional coating as disclosedherein. The invention is also directed to compositions obtained usingthese methods.

The compositions of multiparticulates obtained using air jet sieving andmethods thereof are not limited to the particular embodiments disclosedherein. Air jet sieving can be used for any composition ofmultiparticulates intended for oral use in order to remove fineparticles (e.g., particles which may be aspirated into the lungs).Accordingly, the present invention is directed to compositions andmethods of preparing a multiparticulate formulations for oral deliverycomprising preparing a multiparticulate composition and air jet sievingthe composition to remove particles of less than about 10 μm, less thanabout 50 μm or less than about 100 μm. In preferred embodiments,particles larger than about 500 μm or larger than about 1 mm are alsoremoved from the composition. Preferably, multiple unit doses of thecomposition are then placed in an oral delivery device capable ofmetering a unit dose of the composition for oral delivery. Thesecompositions can be coated (e.g. for sustained release or tastemasking)before air jet sieving, after air jet sieving or not coated at all. Thecoated embodiments can be single or multiple coated (e.g., as disclosedherein).

The use of an air jet sieve is beneficial as the standard sievingtechniques used with screens and meshes may not separate all of thedesired fine particles as the fine particles may adhere to the surfaceof larger particles and thus not separate during the sieving process.The air jet sieving process utilizes a negative pressure to drawparticles below a particular size range down through an appropriatescreen or mesh. In another embodiment, there is a combination of adownward negative pressure and an upward positive pressure whichfacilitates the de-agglomeration of the different particle sizes. Inother embodiments, the upward pressure can be introduced upwards from arotating wand. An apparatus utilizing a negative downward pressure andan upward positive pressure through a rotating wand is a Micron Air JetSieve MAJS I/II manufactured by Hosakawa.

In order to facilitate swallowing of a unit dose of the presentformulation, excipient should be kept to a minimum in order to reducethe mass of the dose. Therefore, in preferred embodiments of the presentinvention, the drug particles comprise at least about 40% drug, at leastabout 50% drug, at least about 60% drug, at least about 80% drug, or atleast about 90% drug.

In preferred embodiments, the core comprises drug coated with excipient;drug interdispersed in excipient; a combination thereof or drug coatedonto excipient, e.g., drug coated inert beads. The core of drug andexcipient is then overcoated with a functional coating. This is notlimiting however, as it is contemplated that single coated particles andcores containing only drug (with at least one coating) are contemplatedby the invention, as long as the desired functional characteristics aremet. In preferred embodiments, the core is formed by mixing drug withexcipient (e.g. a binder such as polyvinylpyrrolidone) to form agranulate which is then sieved and coated with further excipient (e.g.ethylcellulose). These cores can then be coated with a functionalcoating (e.g. microcrystalline cellulose).

In certain embodiments, wet granulation techniques can be used toprepare cores with the drug interdispersed in excipient. Utilizing wetgranulation in preparing the core reduces any resultant fine particlesin the final formulation. Reducing the fine particles results in an oralformulation which has decreased potential for pulmonary deposition dueto the presence of respirable fine particles. The application of thefunctional coat of the invention results in a further decrease inrespirable fine particles.

In certain embodiments, melt granulation techniques can be used toprepare the cores with the drug interdispersed in excipient. In certainembodiments, melt granulation of the drug with excipient results in asmaller fraction of respirable fine materials as compared to wetgranulation techniques. In certain embodiments, in order to provide anequivalent reduction of respirable fines with wet granulation techniquesas compared to melt granulation techniques, it is necessary to increasethe amount of functional coat. An increase in functional coat can resultin a delayed drug release with variable batch to batch dissolutionrates. In certain embodiments, final products prepared with a meltgranulation step has minimal batch to batch variability and anacceptable drug release profile, e.g., without an unwanted delay. Aswith wet granulation embodiments, the application of the functional coatof the invention results in a further decrease in respirable fineparticles.

In certain embodiments, melt granulation can be used in preparing thecore in addition to wet granulation. For example, a fine material with alarge surface area would require an increased amount of melt granulationexcipient. In such embodiments, the fine particles can be wet granulatedin order to provide large particles with a decreased surface area, whileat the same time, reducing respirable particles. The resultant wetgranulated particles can then be melt granulated with a suitableexcipient, which can result in a further reduction of respirableparticles.

In certain embodiments, melt granulation can be used prior to, or afterthe application of the functional coat. For example, if the functionalcoat is an enteric coating, the melt granulation can be performed beforeapplication of the enteric coat, or enteric coated drug particles can bemelt granulated with the melt granulation excipient. Both alternativeswould result in a reduction of respirable particles as compared to theformulations without the melt granulation before or after theapplication of the enteric coat. In certain embodiments, performing themelt granulation prior to application of the functional coat results ina less variable batch to batch ratio as compared to performing the meltgranulation after the application of the functional coat. In certainembodiments, performing the melt granulation prior to the application ofthe functional coat results in a more acceptable particle sizedistribution for applying the functional coat, due to the increasedreduction of fine particles.

When applying the functional coat, e.g., an enteric coat to the meltgranulated core, it is preferable to have a difference between themelting point of the melt granulation excipient and the film formingtemperature of the coating agent of 20 degrees C. or more, in order toreduce interdispersion of the melt granulated material and thefunctional coat.

Suitable melt granulations excipients for the present invention include,e.g., wax materials such as beeswax, white wax, emulsifying wax,hydrogenated vegetable oil, cetyl alcohol, stearyl alcohol, free waxacids such as stearic acid; esters of wax acids; propylene glycolmonostearate, glyceryl monostearate; and carnauba wax. The wax materialcan be a water insoluble wax material or a non-polymeric wax material.In certain preferred embodiments, the melt granulation excipient isglyceryl monostearate, a glyceryl stearate, glyceryl palmitostearate,glyceryl behenate, stearyl alcohol, stearic acid, or a combinationthereof.

Other suitable melt granulation excipients include polyethylene glycolswhich can have a weight average molecular weight of from about 100 toabout 10,000, from about 200 to about 1000, or from about 200 to about400. Preferably, the polyethylene gycol has a molecular weight of fromabout 4,000 to about 8,000 and most preferably a molecular weight ofabout 6,000.

In certain embodiments, the melt granulation is transferred to a trayfor cooling, rather than cooling the granulation while mixing as coolingthe granulation while mixing may result in fragmentation of thegranules. Such fragmentation can result in an increased percentage ofunwanted respirable fines.

In certain embodiments, the excipient of the core provides a controlledrelease (e.g., a sustained release) of the drug upon gastrointestinaldeposition. For example, the excipient can provide a controlled releaseof the drug upon gastrointestinal deposition to provide a therapeuticeffect for at least 12 hours after oral administration. In otherembodiments, the excipient can provide a controlled release of the drugupon gastrointestinal deposition to provide a therapeutic effect for atleast 24 hours after oral administration.

In other embodiments, the excipient can provide a delayed release (e.g.,via an enteric coating) of the drug upon gastrointestinal deposition,such as delaying release of the drug to effect intestinal absorption fordrugs irritating to the gastric mucosa.

In other embodiments, the excipient can provide tastemasking. This isespecially beneficial for bitter tasting drugs, especially whenadministered to small children. If a dose of drug intended for a childhas a bad taste, the child may spit out the dose resulting in waste anda possible reduction in the amount administered. An overdose is alsopossible as if the dose is administered again, it is possible that thechild already ingested a portion of the previous dose.

In other embodiments, the excipient can include a salivary stimulant topromote the production of saliva to facilitate the swallowing of theunit dose. This is especially useful in patients with xerostomia.

In other embodiments, the excipient can provide a moisture barrier inorder to reduce the coalescence of water on the surface of the particlesand reduce undesirable cohesiveness over a wide range of humidities. Incertain embodiments, the cohesiveness of the particles does notsubstantially change over a humidity gradient from about 20% relativehumidity to about 80% relative humidity. In other embodiments, thecohesiveness of the particles does not substantially change over ahumidity gradient from about 40% relative humidity to about 60% relativehumidity.

The effect of humidity can have a negative impact of the flowability ofparticles (e.g., due to cohesiveness). Flowability of the particles canbe measured by such tests as the Carr consolidation index, the uniaxialcompression test and the Jenike shear test. The tests can be performedover a range of relative humidities in order to evaluate the moistureresistance of the present invention.

The Carr consolidation index is measured as Tapped Density−BulkDensity×100

Tapped Density

The relation between Carr's index and powder flowability is expressed inthe table below: Carr's Index State of Flowability  5-15 Excellent 12-16Good 18-21 Fair 23-35 Poor 33-38 Very Poor >40 Very, Very Poor

In certain embodiments of the invention, the flowability according toCarr's index over a humidity gradient from about 20% relative humidityto about 80% relative humidity is preferably 21 or less, preferably 16or less and most preferably 12 or less. In other embodiments, the Carr'sindex does not change by more than about 20%, preferably does not changeby more than 10%, most preferably does not change by more than 5%, overa humidity from about 20% relative humidity to about 80%. In otherembodiments, the composition has the above characteristics over ahumidity gradient from about 40% relative humidity to about 60% relativehumidity or 10% to about 90% relative humidity.

In the uniaxial compression test, a hollow split cylinder is filled withthe test powder. A force transducer is used to apply force or a weightfrom the top of the cylinder onto the powder to consolidate it in avertical direction for a short known time. The applied consolidationforce (σ₁) is then recorded. Then the hollow split cylinder is removedfrom around the consolidated powder. Thereafter increasing vertical loadis applied onto the powder until the consolidated powder collapses orcrackers. This new weight force (σ_(c)) is noted. The smaller this valueis the better the flowability of the powder. The value (ffc) usuallyknown as the quotient of consolidation stress and the unconfined yieldstrength is then calculated by σ₁ divided by σ_(c)

The larger this value, the better the flowability of the powder. If thevalue is >10, the powder is free flowing. If it is between 4-10, thepowder shows adequate flow.

In certain embodiments of the invention, the flowability according tothe uniaxial compression test over a humidity gradient from about 20%relative humidity to about 80% relative humidity is preferably greaterthan about 4, preferably greater than about 10 and most preferablygreater than about 12. In other embodiments, the uniaxial compressiontest does not change by more than about 20%, preferably does not changeby more than 10%, most preferably does not change by more than 5%, overa humidity from about 20% relative humidity to about 80%, morepreferably. In other embodiments, the composition has the abovecharacteristics over a humidity gradient from about 40% relativehumidity to about 60% relative humidity or 10% to about 90% relativehumidity.

The Jenike shear test involves the use of a cell consisting of a base, aring that rests on the base, a mold ring, a preconsolidation lid andshearing lid. The cell is first filled with the test powder using aspoon. The preconsolidation lid is then placed on the powder and apre-shear stress is applied on it. The sample is then consolidated byapplying a number of 90° twists to the lid. A horizontal shearing forceis then applied to the ring at a rate of 2 mm per minute until theconsolidated powder collapses. The ffc can then be calculated as above.Preferably, the flowability of the powder over a humidity rangeaccording to the Jenike shear test is the same as with respect to theuniaxial test as disclosed above.

In other embodiments, the excipient provides a texture modifier in orderto improve mouthfeel of the unit dose in the mouth. An increase inpalatability would be expected to increase compliance as patients may beunwilling to take multiple or chronic dosing of a formulation which theyperceived to be objectionable.

In other embodiments, the functional coating can have the same affect asdisclosed above with respect to the excipient coating.

For example, the functional coating can provide a controlled or delayedrelease of the drug upon gastrointestinal deposition; the functionalcoating can provide tastemasking; the functional coating can comprise asalivary stimulant; the functional coating can provide a moisturebarrier; or the functional coating can be a texture modifier. Thepresent invention is contemplated to encompass all combinations offunctional coating with particular characteristics of core excipient. Itis also understood that one or more of the functions and characteristicsof the excipient and overcoating can be achieved with a single coating.For example, an overcoat which provides a moisture barrier, may alsoprovide texture modification. The same is true in the core, for example,when the core is coated with an excipient that provides controlledrelease and tastemasking of the underlying drug.

In a preferred embodiment, the functional coating minimizes asperitieson the surface of the particles to provide the beneficialcharacteristics disclosed above, e.g. reduced static and reducedinterlocking.

The desired flow characteristics and reduced adhesion and agglomerationof the multiparticulates of the present invention are better achievedwhen the coating or coatings of the particles have pliability and arenot brittle, with a resistant to chipping. Brittleness can increasesurface asperities and reduce the smoothness of the outer coating.Further, chipping can result in the presence of small particles whichcan aspirated into the lungs. Thus, it is desirous to have a pliabletough film which is deformable (pliable) and resistant to chipping(tough).

The pliable tough film of the present invention can be achieve by themanipulation of the process and materials of the coating. In certainembodiments, a plasticizer can be used in the functional coating inorder to make the particles pliable.

Also, the desired pliable tough film can be obtained by minimallyincluding or not including ingredients which can promote brittleness ofthe coating. In certain embodiments of the invention, the use of lakesand opacifiers are minimally used or not used at all as the increaseduse of such ingredients can promote brittleness. In certain embodiments,a colorant which is not a lake or an opacifier can be used and the lakeor opacifier is not used at all in order to maintain the integrity ofthe coating. Other embodiments are directed to including plasticizer andcoloring agents in a ratio which results in a coating having a desiredpliability and non-brittleness.

In certain preferred embodiments of the invention, the multiparticulatedosage form has minimal adhesion and non-agglomeration over a broadrange of humidity. A low humidity dry environment tends to promoteadhesion and agglomeration of particles due to electrostatic forces. Thefunctional coating of the present invention can provide a smooth surfaceto the particles in order to reduce the accumulation of charge inprotrusions and to keep the dosage form from having increased particleto particle interaction.

Likewise, an environment of increased humidity can promote adhesion ofparticles due to surface tension of water accumulating of the surface ofthe particles. The functional coating of the present invention can alsoprovide a surface to the particles in order to reduce the coalescence ofwater on the surface and thus reducing surface tension and particle toparticle interaction. This concept of decreased coalescence of water canbe in addition to, or separate from the embodiment which reduces theaccumulation of charge on the particles. FIG. 1 is a representativegraph of typical powders plotting stickiness versus humidity. FIG. 2 isa representative graph of particles of the present invention, graphingstickiness versus humidity.

As previously discussed, the functional coating and the core excipientcan provide overlapping characteristics. The following representativematerials are meant to be used (i) in the functional overcoat of thecore; (ii) the core excipient coat over the drug; (iii) interdispersedwith then drug or (iv) any combination of (i), (ii) and (iii).

Controlled release materials useful in the present invention arepreferably hydrophobic materials. The hydrophobic materials can beselected from the group consisting of an acrylic polymer, a cellulosicmaterial, shellac, zein and mixtures thereof.

Preferably the hydrophobic material is an acrylic polymer. The acrylicpolymer can be, e.g., selected from, the group consisting of acrylicacid and methacrylic acid copolymers, methacrylic acid copolymers,methyl methacrylate copolymers, ethoxyethyl methacrylates, cynaoethylmethacrylate, methyl methacrylate, copolymers, methacrylic acidcopolymers, methyl methacrylate copolymers, methyl methacrylatecopolymers, methyl methacrylate copolymers, methacrylic acid copolymer,aminoalkyl methacrylate copolymer, methacrylic acid copolymers, methylmethacrylate copolymers, poly(acrylic acid), poly(methacrylic acid,methacrylic acid alkylamide copolymer, poly(methyl methacrylate),poly(methacrylic acid) (anhydride), methyl methacrylate,polymethacrylate, methyl methacrylate copolymer, poly(methylmethacrylate), poly(methyl methacrylate) copolymer, polyacrylamide,aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride),glycidyl methacrylate copolymers and mixtures thereof.

When the controlled release material is a cellulosic material, thecellulosic material is, e.g., selected from the group consisting ofcellulose esters, cellulose diesters, cellulose triesters, celluloseethers, cellulose ester-ether, cellulose acylate, cellulose diacylate,cellulose triacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, cellulose acetate propionate, cellulose acetate butyrate andmixtures thereof.

Particularly preferred controlled release materials are ethylcellulose,polymethacrylates, e.g. Eudragit RL and RS, glyceryl behenate,methylcellulose and sodium carboxymethylcellulose.

In other embodiments of the invention, the controlled release materialcomprises a lacquer material. The lacquer material can be selected,e.g., from the group consisting of corn oil, cottonseed oil, menhadenoil, pine oil, peanut oil, safflower oil, sesame oil, soybean oil,linseed oil and mixtures thereof. Other suitable oils useful as lacquermaterials include fatty acids of C8-C20 oils which can be saturated,unsaturated, glycerides thereof, and combination thereof. Preferably asalt such as magnesium stearate is included. Other suitable oils usefulas lacquer materials include branched or polycarboxylated oils such aslinoleic acid, linolenic acid, oleic acid and combinations thereof.Saturated oils from the following table are also useful as lacqueragents: Systematic Trivial Shorthand Molecular Melting point name namedesignation wt. (° C.) Octanoic Caprylic  8:0 144.2 16.7 Decanoic Capric10:0 172.3 31.6 Dodecanoic Lauric 12:0 200.3 44.2 Tetradecanoic Myristic14:0 228.4 53.9 Hexadecanoic Palmitic 16:0 256.4 63.1 HeptadecanoicMargaric 17:0 270.4 61.3 Octadecanoic Stearic 18:0 284.4 69.6 EicosanoicArachidic 20:0 412.5 75.3 Docosanoic Behenic 22:0 340.5 79.9Tetracosanoic Lignoceric 24:0 368.6 84.2

The use of lacquer agents may not release the drug of themultiparticulates. Therefore it may be necessary to include a channelingagent in an amount sufficient to provide the desired release of thedrug, e.g., over 12 or 24 hours. Suitable channeling agents includepolyvinylpyrrolidone, polyethyleneglycols, dextrose, sucrose, mannitol,xylitol and lactose. Antioxidants can also be added in order to reducepolymerization which leads to increased hardness.

The use of lacquer agents is beneficial as it reduces the amount ofexcipient needed to provide a controlled release of the drug from theparticles of the present invention. In certain embodiments, less thanabout 1% lacquer is needed in the formulation (w/w) to provide thedesired effect. Accordingly, as only a small amount of lacquer materialis needed, it is preferably mixed with a dispersing agent. Suitabledispersing agents include colloidal silicone dioxide, talc, kaolin,silicone dioxide, colloidal calcium carbonate, bentonite, Fuller'searth, magnesium aluminum silicate and mixtures thereof. A preferredlacquer material is linseed oil with kaolin as a dispersing agent.

The lacquer material can be granulated with the drug in order to providecontrolled release matrices or can coat the drug particulates. The useof lacquer materials is disclosed as providing controlled release inmultiparticulate dosage forms. However, it also contemplated by thepresent invention that the use of lacquer agents with optionalchanneling agents and dispersing agents can also be used in solid dosageforms such as tablets. For example, an immediate release tablet core canbe coated with sustained release coating comprising a lacquer agent asdisclosed above with an optional channeling agent and dispersing agent.In these embodiments as well, a preferred lacquer material is linseedoil with kaolin as a dispersing agent.

Preferably, the delayed release material used in the present inventionare enteric polymers. The enteric polymers can be selected from, e.g.,the group consisting of methacrylic acid copolymers, cellulose acetatephthalate, hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate,cellulose acetate trimellitate, carboxymethylethyl-cellulose andmixtures thereof. Particularly preferred enteric polymers arepolymethacrylates such as Eudragit US polymers, cellulose acetatephthalate, polyvinyl acetate phthalate, bydroxypropyl-methylcellulosephthalate and shellac. Sureteric™ is an example of a polyvinyl acetatephthalate based entereic coating. Acryl-eze™ is an example of amethacrylic acid copolymer based enteric coating.

The tastemasking material of the present material can be selected from,e.g., the group consisting of water-soluble sweetening agents,water-soluble artificial sweeteners, dipeptide based sweeteners andmixtures thereof. The water-soluble sweetening agent can be selectedfrom, e.g., the group consisting of monosaccharides, disaccharides andpolysaccharides such as xylose, ribose, glucose, mannose, galactose,fructose, dextrose, sucrose, sugar, maltose, partially hydrolyzedstarch, or corn syrup solids and sugar alcohols such as sorbitol,xylitol, or mannitol and mixtures thereof. The water-soluble artificialsweetener material of the present invention is selected from, e.g., thegroup consisting of soluble saccharin salts, such as sodium or calciumsaccharin salts, cyclamate salts, acesulfam-K, the free acid form ofsaccharin and mixtures thereof. The dipeptide based sweetener ispreferably L-aspartyl L-phenylalanine methyl ester. Particularlypreferred taste masking agents are glyceryl behenate, glycerylpalmitostearate, ethylcellulose and polymethacrylates such as EudragitE, EPO and RD.

In other embodiments of the invention, the multiparticulates cancomprise an effervescent compound or composition which provides apleasing organoleptic effect which can substantially mask the taste ofunpalatable active ingredients in the powder. The effervescent actionalso acts as a stimulant to saliva production. Effervescent agentsinclude compounds which evolve gas. The preferred effervescent agentsevolve gas by means of chemical reactions which take place upon exposureto a liquid such as saliva in the mouth. This bubble or gas generatingchemical reaction is most often the result of the reaction of an acid(e.g. the saliva stimulant acids listed above) and an alkali metalcarbonate/dicarbonate or base. The reaction of these two general classesof compounds produces carbon dioxide gas upon contact with saliva.

Other salivary stimulant of the present invention can be selected from,e.g., food acids, acid anhydrides and acid salts. Food acids includetartaric acid, malic acid, fumaric acid, adipic acid, and succinic acidsand fruit acids, e.g., citric acid. Acid anhydrides of the abovedescribed acids may also be used. Acid salts may include sodium,dihydrogen phosphate, disodium dihydrogen pyrophosphate, acid citratesalts and sodium acid sulfite.

The moisture barrier material of the present invention can be, e.g.,selected from the group consisting of acacia gum, acrylic acid polymersand copolymers (polyacrylamides, polyacryldextrans, polyalkylcyanoacrylates, polymethyl methacrylates), agar-agar, agarose, albumin,alginic acid and alginates, carboxyvinyl polymers, cellulose derivativessuch as cellulose acetate, polyamides (nylon 6-10,poly(adipyl-L-lysines, polyterephthalamides andpoly-(terephthaloyl-L-lysines)), poly-.epsilon.-caprolactam,polydimethylsiloxane, polyesters, poly(ethylene-vinyl acetate),polyglycolic acid, polyactic acid and its copolymers, polyglutamic acid,polylysine, polystyrene, shellac, xanthan gum, anionic polymers ofmethacrylic acid and methacrylic acid esters, hydroxyalkylcelluloses andmixtures thereof. In certain embodiments, the moisture barrier materialis a hydroxyalkylcellulose such as hydroxypropylmethylcellulose; acellulosic material such as microcrystalline cellulose; carrageenan; ormixtures thereof. Particularly preferred moisture barrier materials aremicrocrystalline cellulose/carrageenan-based coating systems, such asLustreClear, ethylcellulose; such as Aquacoat ECD (formulated as a 50:50mixture with hydroxypropylmethylcellulose) and polyvinyl alcohol basedsystems such as Opadry AMB. The above disclosed lacquer agents can alsobe used as moisture barriers.

The texture modifier material of the present invention can be, e.g.,selected from the group consisting of acacia gum, acrylic acid polymersand copolymers (polyacrylamides, polyacryldextrans, polyalkylcyanoacrylates, polymethyl methacrylates), agar-agar, agarose, albumin,alginic acid and alginates, carboxyvinyl polymers, cellulose derivativessuch as cellulose acetate, polyamides (nylon 6-10,poly(adipyl-L-lysines, polyterephthalamides andpoly-(terephthaloyl-L-lysines)), poly-epsilon.-caprolactam,polydimethylsiloxane, polyesters, poly(ethylene-vinyl acetate),polyglycolic acid, polyactic acid and its copolymers, polyglutamic acid,polylysine, polystyrene, shellac, xanthan gum, anionic polymers ofmethacrylic acid and methacrylic acid esters, hydroxyalkylcelluloses andmixtures thereof. Particularly preferred texture modifiers arecellulose, e.g., carboxymethyl cellulose and microcrystalline cellulose;polydextrose; modified starch; dextrins; gums, e.g. xanthan, guar,locust-bean, carrageenan and alginates; pectins; maltodexrins andcarbomers.

Materials which can be used to obtain a pliable and/or chip resistantcoating of the present invention can be selected, e.g., from the groupconsisting of acacia gum, alginic acid and alginates,carboxymethylcellulose, ethylcellulose, gelatine,hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose,xanthan gum, pectin, tragacanth, microcrystalline cellulose,hydroxyethylcellulose, ethylhydroxyethylcellulose, sodiumcarboxymethylcellulose, polyethylene glycols, polyvinylpyrrolidone,polyvinyl alcohol, polyacrylic acid, gum arabic, lactose, starch (wheat,maize, potato and rice starch), sucrose, glucose, mannitol, sorbitol,xylitol, stearic acid, hydrogenated cottonseed oil, hydrogenated castoroil, vinylpyrrolidone-vinyl acetate copolymers, fructose,methylhydroxyethylcellulose, agar-agar, carrageenan, karaya gum,chitosan, starch hydrolysates and mixtures thereof. Especially preferredmaterials are plasticizers which can be selected from, e.g., the groupconsisting of dibutyl sebacate, diethyl phthalate, triethyl citrate,tibutyl citrate, triacetin, benzyl benzoate, chlorobutanol, sorbitol,glycerol, polyethyleneglycol and mixtures thereof.

With respect to decreasing static in the particles, it was disclosedabove that a smooth surface can be provided to the surface of theparticles in order to avoid charge gathering and decrease adhesion andagglomeration of particles. Decreasing charge can also be effected onthe particles of the present invention by including a conductive polymerinto the functional coat. Examples of conductive polymers arepolypyrroles, polythiophene, poly(p-phenylene), poly(phenylene vinylene)and trans-polyacetylene. These are rigid polymers and may require theaddition of a plasticizer in order to provide a more flexible coating. Aless rigid conductive polymer is polyanilene, although inclusion of aplasticizer is still preferable.

A preferred method to decrease charge on the multiparticulates is by theelectrohydrodynamic spraying of a viscous and highly conductivepolyvinyl alcohol aqueous solution, as described in Electrospraying of ahighly conductive and viscous liquid, Speranza et al. Journal ofElectrostatics, (51) p494, hereby incorporated by reference.

Conductive polymers are further discussed in U.S. Pat. Nos. 6,060,116and 5,268,407, hereby incorporated by reference with respect to theircombination with the multiparticulate formulations of the presentinvention.

Another method of reducing charge in the present invention is to includein the multiparticulates, or provide a final coat of compounds selectedfrom magnesium stearate and the like, surfactants such as sodium laurylsulphate and combinations thereof. In order for these materials to bemost effective, they would be included as a final coat with robustmixing in order to provide an even coat on the particles.

Classes of drugs which are suitable in the present invention includeantacids, anti-inflammatory substances, coronary dilators, cerebraldilators, peripheral vasodilators, anti-infectives, psychotropics,anti-manics, stimulants, anti-histamines, laxatives, decongestants,vitamins, gastro-intestinal sedatives, anti-diarrheal preparations,anti-anginal drugs, vasodilators, anti-arrhythmics, anti-hypertensivedrugs, vasoconstrictors and migraine treatments, anti-coagulants andanti-thrombotic drugs, analgesics, anti-pyretics, hypnotics, sedatives,anti-emetics, anti-nauseants, anti-convulsants, neuromuscular drugs,hyper- and hypoglycemic agents, thyroid and anti-thyroid preparations,diuretics, anti-spasmodics, uterine relaxants, mineral and nutritionaladditives, anti-obesity drugs, anabolic drugs, erythropoietic drugs,anti-asthmatics, bronchodilators, expectorants, cough suppressants,mucolytics, drugs affecting calcification and bone turnover andanti-uricemic drugs.

Specific drugs include gastro-intestinal sedatives such asmetoclopramide and propantheline bromide; antacids such as aluminumtrisilicate, aluminum hydroxide, ranitidine and cimetidine;anti-inflammatory drugs such as phenylbutazone, indomethacin, naproxen,ibuprofen, flurbiprofen, diclofenac, dexamethasone, prednisone andprednisolone; coronary vasodilator drugs such as glyceryl trinitrate,isosorbide dinitrate and pentaerythritol tetranitrate; peripheral andcerebral vasodilators such as soloctidilum, vincamine, naftidrofuryloxalate, co-dergocrine mesylate, cyclandelate, papaverine and nicotinicacid; anti-infective substances such as erythromycin stearate,cephalexin, nalidixic acid, tetracycline hydrochloride, ampicillin,flucloxacillin sodium, hexamine mandelate and hexamine hippurate;neuroleptic drugs such as flurazepam, diazepam, temazepam,amitryptyline, doxepin, lithium carbonate, lithium sulfate,chlorpromazine, thioridazine, trifluperazine, fluphenazine,piperothiazine, haloperidol, maprotiline hydrochloride, imipramine anddesmethylimipramine; central nervous stimulants such as methylphenidate,ephedrine, epinephrine, isoproterenol, amphetamine sulfate andamphetamine hydrochloride; antihistamic drugs such as diphenhydramine,diphenylpyraline, chlorpheniramine and brompheniramine; anti-diarrhealdrugs such as bisacodyl and magnesium hydroxide; the laxative drug,dioctyl sodium sulfosuccinate; nutritional supplements such as ascorbicacid, alpha tocopherol, thiamine and pyridoxine; anti-spasmodic drugssuch as dicyclomine and diphenoxylate; drugs affecting the rhythm of theheart such as verapamil, nifedipine, diltiazem, procainamide,disopyramide, bretylium tosylate, quinidine sulfate and quinidinegluconate; drugs used in the treatment of hypertension such aspropranolol hydrochloride, guanethidine monosulphate, methyldopa,oxprenolol hydrochloride, captopril and hydralazine; drugs used in thetreatment of migraine such as ergotamine; drugs affecting coagulabilityof blood such as epsilon aminocaproic acid and protamine sulfate;analgesic drugs such as acetylsalicylic acid, acetaminophen, codeinephosphate, codeine sulfate, oxycodone, dihydrocodeine tartrate,oxycodeinone, morphine, heroin, nalbuphine, butorphanol tartrate,pentazocine hydrochloride, cyclazacine, pethidine, buprenorphine,scopolamine and mefenamic acid; anti-epileptic drugs such as phenyloinsodium and sodium valproate; neuromuscular drugs such as dantrolenesodium; substances used in the treatment of diabetes such astolbutamide, disbenase glucagon and insulin; proteins and peptides suchas heparin and calcitonin, drugs used in the treatment of thyroid glanddysfunction such as triiodothyronine, thyroxine and propylthiouracil,diuretic drugs such as furosemide, chlorthalidone, hydrochlorthiazide,spironolactone and triamterene; the uterine relaxant drug ritodrine;appetite suppressants such as fenfluramine hydrochloride, phentemmineand diethylproprion hydrochloride; anti-asthmatic and bronchodilatordrugs such as aminophylline, theophylline, salbutamol, orciprenalinesulphate and terbutaline sulphate; expectorant drugs such asguaiphenesin; cough suppressants such as dextromethorphan and noscapine;mucolytic drugs such as carbocisteine; anti-septics such ascetylpyridinium chloride, tyrothricin and chlorhexidine; decongestantdrugs such as phenylpropanolamine and pseudoephedrine; hypnotic drugssuch as dichloralphenazone and nitrazepam; anti-nauseant drugs such aspromethazine theoclate; haemopoietic drugs such as ferrous sulphate,folic acid and calcium gluconate; uricosuric drugs such assulphinpyrazone, allopurinol and probenecid; and calcification affectingagents such as biphosphonates, e.g., etidronate, pamidronate,alendronate, residronate, teludronate, clodronate and alondronate.

Drugs which possess taste and/or odor characteristics which, whenadministered orally without any excipients, render the drug ortherapeutic agent unpalatable to a subject and would be candidates fortaste masking in the present invention include, but are not limited to,H₂ receptor antagonists, antibiotics, analgesics, cardiovascular agents,peptides or proteins, hormones, anti-migraine agents, anti-coagulantagents, anti-emetic agents, anti-hypertensive agents, narcoticantagonists, chelating agents, anti-anginal agents, chemotherapy agents,sedatives, anti-neoplastics, prostaglandins, antidiuretic agents and thelike. Typical drugs include but are not limited to nizatidine,cimetidine, ranitidine, famotidine, roxatidine, etinidine, lupitidine,nifentidine, niperitone, sulfotidine, tuvatidine, zaltidine,erythomycin, penicillin, ampicillin, roxithromycin, clarithromycin,psylium, ciprofloxacin, theophylline, nifedipine, prednisone,prednisolone, ketoprofen, acetaminophen, ibuprofen, dexibuprofenlysinate, flurbiprofen, naproxen, codeine, morphine, sodium diclofenac,acetylsalicylic acid, caffeine, pseudoephedrine, phenylpropanolamine,diphenhydramine, chlorpheniramine, dextromethorphan, berberine,loperamide, mefenamic acid, flufenamic acid, astemizole, terfenadine,certirizine, phenyloin, guafenesin, N-acetylprocainamide HCl,pharmaceutically acceptable salts thereof and derivatives thereof.

Particularly preferred agents include antibiotics such asclarithromycin, amoxicillin erythromycin, ampicillin, penicillin,cephalosporins, e.g., cephalexin, pharmaceutically acceptable saltsthereof and derivatives thereof.

Other preferred agents are acetaminophen and NSAIDS such as ibuprofen,indomethacin, aspirin, diclofenac and pharmaceutically acceptable saltsthereof.

The size of the unit dose is dependent on the amount of drug needed toprovide the intended therapeutic effect and the amount of anypharmaceutically acceptable excipient which may be necessary. Typically,a unit dose of from about 0.01 mg to about 1.5 g would be sufficient tocontain a therapeutically effective amount of the drug to be delivered,however, this range is not limiting and can be smaller or higher,depending on the amount of drug and excipient that is necessary.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS EXAMPLE 1 Controlled-ReleasePropranolol HCl

Step 1: Granulation of Propranolol HCl

Prior to commencing granulation of the Propranolol HCl, the vessel ofthe MP Micro is pre-warmed by heating at 70° C. for 15 minutes with anominal airflow of 6.0 m³/Hr. 76 g of Propranolol HCl and 4 g of PVPK-30 is added to the vessel and the process temperature set to 70° C.The airflow is then increased until the product is fluidised. Once aconstant temperature is achieved within the powder bed, spraygranulation of the product is commenced by the introduction of distilledwater as the granulation fluid. An atomising pressure of 2 bar is used.

Once the material is granulated the addition of the granulation fluid isstopped and the powder bulk is dried. The end point of the dryingprocess is indicated by a constant temperature within the powder bed. Atthis point the temperature of the inlet air is reduced to 25° C. and thebulk material removed. Once cooled the material is screened through a250 micron sieve then air jet sieved to remove particles below 100microns.

Step 2: Spray Coating With Surelease

An aqueous dispersion of Surelease is prepared by diluting to 15% w/wsolids (i.e. 60% Surelease dispersion and 40% distilled or deionisedwater) and stirred using a low shear mixer for approximately 15 minutes.With the precision coater module attached the vessel is preheated at 70°C. for 15 minutes with a nominal airflow of 6.0 m³¹ Hr. 60 g of thegranulated Propranolol HCl is returned to the MP Micro and the processtemperature set at 70° C. to achieve a product temperature of 40-45° C.The airflow is increased until the product is fluidised. Once thematerial is equilibrated within the vessel, a constant temperature isreached within the powder bed. The material is then sprayed with theSurelease dispersion to achieve a 10-30% wt. gain depending on thedesired release profile at a spraying rate of 1.0 g/min with anatomising air pressure of 2 bar. Once the desired weight of Sureleasecoating are added to the granules the pump and the atomising air arestopped and the material dried until the powder bed reaches a constanttemperature. At this point the inlet air temperature is reduced to 25°C. and the operation stopped.

Step 3: Overcoating with LustreClear

A 9% w/w dispersion of LustreClear is prepared as follows:

-   -   The necessary quantity of LustreClear film coating system is        accurately weighed out.    -   The necessary quantity of water is accurately weighed into the        mixing vessel.    -   With the propeller in the centre and as close to the bottom of        the vessel as possible, the water is stirred to form a vortex        without drawing air into the liquid.    -   The LustreClear powder is steadily added to the vortex, avoiding        powder flotation on the liquid surface.    -   The stirrer speed is increased in order to maintain the vortex        as required.    -   After all the LustreClear is added, the dispersion is then mixed        for a further 3 hours.    -   The dispersion is then left for a further 2 hours before use.

Residual Surelease is removed from the spray nozzle by rapidly flushingthrough with the 9% w/w dispersion LustreClear. The precision coatermodule is washed and then dried by heating at 85° C. for 15 minutes witha nominal airflow of 6.0 m³/Hr. The Surelease coated granules are placedinto the precision coater and are fluidised using the same conditions asfor the addition of Surelease. Once the material is equilibrated withinthe vessel, a constant temperature is reached within the powder bed. Atthis point the granules are coated with the 9% w/w dispersion ofLustreClear at a rate of 1.0 g/min. Once a coating of 4-30% wt. gain isapplied, spraying of the LustreClear dispersion is stopped and thematerial dried until a constant temperature is observed within thepowder bed. At this point the airflow temperature is reduced to 25° C.and the bulk material removed, allowing it to cool.

EXAMPLE 2 Enteric Coated Indomethacin

Step 1: Granulation of Indomethacin

Before commencing the granulation of the Indomethacin, the vessel of theMP Micro is pre-warmed by heating at 70° C. for 15 minutes with anominal airflow of 6.0 m³/Hr. 76 g of Indomethacin and 4 g of PVP K-30is added to the vessel and the process temperature set to 70° C. Theairflow is then increased until the product is fluidised. Once aconstant temperature is achieved within the powder bed, spraygranulation of the product is commenced by the introduction of distilledwater as the granulation fluid. An atomising pressure of 2 bar is used.

Once the material is granulated, the addition of the granulation fluidis stopped and the powder bulk is dried. The end point of the dryingprocess is indicated by a constant temperature within the powder bed. Atthis point the temperature of the inlet air is reduced to 25° C. and thebulk material removed. Once cooled the material is screened through a250 microns sieve and air jet sieved to remove particles below 100microns. 156

Step 2: Spray Coating With Sureteric

Before applying the Sureteric coat, a 10% w/w dispersion of Opadry II(white) is applied to the granulated Indomethacin to a 2% wt. gain. The10% w/w dispersion of Opadry II is prepared as follows:

The necessary quantity of Opadry II film coating system is accuratelyweighed out.

The necessary quantity of water is accurately weighed into the mixingvessel.

With the propeller in the centre and as close to the bottom of thevessel as possible, the water is stirred to form a vortex withoutdrawing air into the liquid.

The Opadry II powder is steadily added to the vortex, avoiding powderflotation on the liquid surface.

The stirrer speed is increased in order to maintain the vortex asrequired.

After all the Opadry II system is added, the mixer speed is reduced tonearly eliminate the vortex. The dispersion is then mixed for a further45 minutes.

With the precision coater module attached the vessel is preheated at 70°C. for 15 minutes with a nominal airflow of 6.0 m³/Hr. 60 g of thegranulated Indomethacin is returned to the MP Micro and the processtemperature set at 75° C. to achieve a product temperature of 40-45° C.The airflow is increased until the product is fluidised. Once thematerial is equilibrated within the vessel, a constant temperature isreached within the powder bed. The 10% w/w dispersion is then sprayedonto the Indomethacin granules at a rate of 0.2 g/min with an atomisingair pressure of 2 bar. Once the desired weight of Opadry II is appliedto the granules the pump and the atomising air are stopped and thematerial is dried until the powder bed reaches a constant temperature.At this point the inlet air temperature is reduced to 25° C. and theoperation stopped.

A15% w/w Sureteric dispersion (containing 0.33% w/w simethicone, as ananti-foaming agent) is prepared as follows:

The necessary quantity of Sureteric powder is accurately weighed out.

The necessary quantity of water is accurately weighed into the mixingvessel.

With the propeller in the centre and as close to the bottom of thevessel as possible, the water is stirred to form a vortex withoutdrawing air into the liquid.

The necessary quantity of anti-foaming emulsion is weighed out and addedto the water.

The Sureteric powder is steadily added to the vortex, whilst maintaininga vigorous vortex.

The mixer speed is reduced to nearly eliminate the vortex and thedispersion mixed for a further 45 minutes.

Prior to coating, the dispersion is passed through a 250 micron sieve.

Residual Opadry II dispersion is removed from the spray nozzle byrapidly flushing through with the 10% w/w dispersion of Sureteric. Theprecision coater module is washed and then dried by heating at 85° C.for 15 minutes with a nominal airflow of 6.0 m³/Hr. The Opadry II coatedgranules are placed into the precision coater and are fluidised usingthe same conditions as for the addition of Opadry II. Once the materialis equilibrated within the vessel, a constant temperature is reachedwithin the powder bed. At this point the granules are coated with the10% w/w dispersion of Sureteric at a rate of 1.0 g/min. Once a 10-20%wt. gain coating is applied, spraying of the Sureteric dispersion isstopped and the material dried until a constant temperature is observedwithin the powder bed. At this point the airflow temperature is reducedto 25° C. and the bulk material removed, allowing it to cool.

Step 3: Overcoating With LustreClear

A 9% w/w dispersion of LustreClear is prepared as follows:

The necessary quantity of LustreClear film coating system is accuratelyweighed out.

The necessary quantity of water is accurately weighed into the mixingvessel.

With the propeller in the centre and as close to the bottom of thevessel as possible, the water is stirred to form a vortex withoutdrawing air into the liquid.

The LustreClear powder is steadily added to the vortex, avoiding powderflotation on the liquid surface.

The stirrer speed is increased in order to maintain the vortex asrequired.

After all the LustreClear is added, the dispersion is then mixed for afurther 3 hours.

The dispersion is then left for a further 2 hours before use.

Residual Sureteric is removed from the spray nozzle by rapidly flushingthrough with the 9% w/w dispersion of LustreClear. The precision coatermodule is washed and then dried by heating at 85° C. for 15 minutes witha nominal airflow of 6.0 m³/Hr. The enteric-coated granules are placedinto the precision coater and are fluidised using the same conditions asfor the addition of Sureteric. Once the material is equilibrated withinthe vessel, a constant temperature is reached within the powder bed. Atthis point the granules are coated with the 9% w/w dispersion ofLustreClear at a rate of 1.0 g/min. Once a coating of 4-30% wt. gain isapplied, spraying of the LustreClear dispersion is stopped and thematerial dried until a constant temperature is observed within thepowder bed. At this point the airflow temperature is reduced to 25° C.and the bulk material removed, allowing it to cool.

EXAMPLE 3 Controlled-Release Clarithromycin

Step 1: Granulation of Clarithromycin

Prior to commencing granulation of the Clarithromycin, the vessel of theMP Micro is pre-warmed by heating at 70° C. for 15 minutes with anominal airflow of 6.0 m³/Hr. 76 g of Clarithromycin and 4 g of PVP K-30is added to the vessel and the process temperature set to 70° C. Theairflow is then increased until the product is fluidised. Once aconstant temperature is achieved within the powder bed, spraygranulation of the product is commenced by the introduction of distilledwater as the granulation fluid. An atomising pressure of 2 bar is used.

Once the material is granulated the addition of the granulation fluid isstopped and the powder bulk is dried. The end point of the dryingprocess is indicated by a constant temperature within the powder bed. Atthis point the temperature of the inlet air is reduced to 25° C. and thebulk material removed. Once cooled the material is screened through a250 micron sieve then air jet sieved to remove particles below 100microns.

Step 2: Spray Coating With Combined Eudragit RS/RL-100

An aqueous dispersion of Eudragit RS/RL-100 is prepared byreconstituting both materials separately as follows:

-   -   The necessary quantity of Eudragit is accurately weighed out,        necessary to prepare a 12.5% w/w aqueous dispersion.    -   The necessary quantity of water is accurately weighed into the        mixing vessel.    -   With the propeller in the centre and as close to the bottom of        the vessel as possible, the water is stirred to form a vortex        without drawing air into the liquid.    -   The Eudragit powder is steadily added to the vortex, avoiding        powder floatation on the liquid surface.    -   The stirrer speed is increased in order to maintain the vortex        as required.    -   Once all of the Eudragit is added, the mixer speed is reduced to        nearly eliminate the vortex. The dispersion is then mixed for a        further 120 minutes.    -   The dispersion is then diluted further by the addition of 10-25%        of a suitable plasticiser (in this case Triethyl Citrate)

Once the Eudragit RS-100 and RL-100 is prepared, they are mixed atvarying ratios (e.g. 1:3, 1:1 and 3:1) to produce the required releaseprofile. With the precision coater module attached the vessel ispreheated at 70° C. for 15 minutes with a nominal airflow of 6.0 m³/Hr.60 g of the granulated Clarithromycin is returned to the. MP Micro andthe process temperature set at 95° C. The airflow is increased until theproduct is fluidised. Once the material is equilibrated within thevessel, a constant temperature is reached within the powder bed. Thematerial is then sprayed with the Eudragit RS/RL-100 dispersion toachieve a 6-30% wt. gain depending on the desired release profile at aspraying rate of 1.0 g/min with an atomising air pressure of 2 bar.

Once the desired weight of Eudragit coating is added to the granules,the pump and the atomising air are stopped and the material dried untilthe powder bed reaches a constant temperature. At this point the inletair temperature is reduced to 25° C. and the operation stopped.

Step 3: Overcoating With LustreClear

A 9% w/w dispersion of LustreClear is prepared as follows:

-   -   The necessary quantity of LustreClear film coating system is        accurately weighed out.    -   The necessary quantity of water is accurately weighed into the        mixing vessel.    -   With the propeller in the centre and as close to the bottom of        the vessel as possible, the water is stirred to form a vortex        without drawing air into the liquid.    -   The LustreClear powder is steadily added to the vortex, avoiding        powder flotation on the liquid surface.    -   The stirrer speed is increased in order to maintain the vortex        as required.    -   After all the LustreClear is added, the dispersion is then mixed        for a further 3 hours.    -   The dispersion is then left for a further 2 hours before use.

Residual Eudragit is removed from the spray nozzle by rapidly flushingthrough with the 9% w/w dispersion LustreClear. The precision coatermodule is washed and then dried by heating at 85° C. for 15 minutes witha nominal airflow of 6.0 m³/Hr. The Eudragit coated granules are placedinto the precision coater and are fluidised using the same conditions asfor the addition of Eudragit. Once the material is equilibrated withinthe vessel, a constant temperature is reached within the powder bed. Atthis point the granules are coated with the 9% w/w dispersion ofLustreClear at a rate of 1.0 g/min. Once a coating of 4-30% wt. gain isapplied spraying of the LustreClear dispersion is stopped and thematerial dried until a constant temperature is observed within thepowder bed. At this point the airflow temperature is reduced to 25° C.and the bulk material removed, allowing it to cool.

EXAMPLE 4 Controlled-Release Enteric-Coated Clarithromycin

Step 1: Granulation of Clarithromycin

Prior to commencing granulation of the Clarithromycin, the vessel of theMP Micro is pre-warmed by heating at 70° C. for 15 minutes with anominal airflow of 6.0 m³/Hr. 76 g of Clarithromycin and 4 g of PVP K-30is added to the vessel and the process temperature set to 70° C. Theairflow is then increased until the product is fluidised. Once aconstant temperature is achieved within the powder bed, spraygranulation of the product is commenced by the introduction of distilledwater as the granulation fluid. An atomising pressure of 2 bar is used.

Once the material is granulated the addition of the granulation fluid isstopped and the powder bulk is dried. The end point of the dryingprocess is indicated by a constant temperature within the powder bed. Atthis point the temperature of the inlet air is reduced to 25° C. and thebulk material removed. Once cooled the material is screened through a250 micron sieve then air jet sieved to remove particles below 100microns.

Step 2: Spray Coating With Combined Eudragit RS/RL-100

An aqueous dispersion of Eudragit RS/RL-100 is prepared byreconstituting both materials separately as follows:

-   -   The necessary quantity of Eudragit is accurately weighed out,        necessary to prepare a 12.5% w/w aqueous dispersion.    -   The necessary quantity of water is accurately weighed into the        mixing vessel.    -   With the propeller in the centre and as close to the bottom of        the vessel as possible, the water is stirred to form a vortex        without drawing air into the liquid.    -   The Eudragit powder is steadily added to the vortex, avoiding        powder floatation on the liquid surface.    -   The stirrer speed is increased in order to maintain the vortex        as required.    -   Once all of the Eudragit is added, the mixer speed is reduced to        nearly eliminate the vortex. The dispersion is then mixed for a        further 120 minutes.    -   The dispersion is then diluted further by the addition of 10-25%        of a suitable plasticiser (in this case Triethyl Citrate)

Once the Eudragit RS-100 and RL-100 is prepared, they are mixed atvarying ratios (e.g. 1:3, 1:1 and 3:1) to produce the required releaseprofile. With the precision coater module attached, the vessel ispreheated at 70° C. for 15 minutes with a nominal airflow of 6.0 m³/Hr.60 g of the granulated Clarithromycin is returned to the MP Micro andthe process temperature set at 70° C. to achieve a product temperatureof 40-45° C. The airflow is increased until the product is fluidised.Once the material is equilibrated within the vessel, a constanttemperature is reached within the powder bed. The material is thensprayed with the Eudragit RS/RL-100 dispersion to achieve a 6-30% wt.gain depending on the desired release profile at a spraying rate of 1.0g/min with an atomising air pressure of 2 bar.

Once the desired weight of Eudragit coating is added to the granules thepump and the atomising air are stopped and the material dried until thepowder bed reached a constant temperature. At this point the inlet airtemperature is reduced to 25° C. and the operation stopped.

Step 3: Spray Coating With Sureteric

Before applying the Sureteric coat, a 10% w/w dispersion of Opadry II(white) is applied to the granulated Clarithromycin to a 2% wt. gain.The 10% w/w dispersion of Opadry II is prepared as follows:

-   -   The necessary quantity of Opadry II film coating system is        accurately weighed out.    -   The necessary quantity of water is accurately weighed into the        mixing vessel.    -   With the propeller in the centre and as close to the bottom of        the vessel as possible, the water is stirred to form a vortex        without drawing air into the liquid.    -   The Opadry II powder is steadily added to the vortex, avoiding        powder flotation on the liquid surface.    -   The stirrer speed is increased in order to maintain the vortex        as required.    -   After all the Opadry II system is added, the mixer speed is        reduced to nearly eliminate the vortex. The dispersion is then        mixed for a further 45 minutes.

With the precision coater module attached the vessel is preheated at 70°C. for 15 minutes with a nominal airflow of 6.0 m³/Hr. 60 g of thegranulated Clarithromycin is returned to the MP Micro and the processtemperature set at 70° C. to achieve a product temperature of 40-45° C.The airflow is increased until the product is fluidised. Once thematerial equilibrated within the vessel, a constant temperature isreached within the powder bed. The 10% w/w dispersion is then sprayedonto the Clrithromycin granules at a rate of 1.0 g/min with an atomisingair pressure of 2 bar. Once the desired weight of Opadry II is appliedto the granules, the pump and the atomising air are stopped and thematerial dried until the powder bed reached a constant temperature. Atthis point the inlet air temperature is reduced to 25° C. and theoperation stopped.

A 15% w/w Sureteric dispersion (containing 0.33% w/w simethicone, as ananti-foaming agent) is prepared as follows:

-   -   The necessary quantity of Sureteric powder is accurately weighed        out.    -   The necessary quantity of water is accurately weighed into the        mixing vessel.    -   With the propeller in the centre and as close to the bottom of        the vessel as possible, the water is stirred to form a vortex        without drawing air into the liquid.    -   The necessary quantity of anti-foaming emulsion is weighed out        and added to the water.    -   The Sureteric powder is steadily added to the vortex, whilst        maintaining a vigorous vortex.    -   The mixer speed is reduced to nearly eliminate the vortex and        the dispersion is mixed for a further 45 minutes.    -   Prior to coating, the dispersion is passed through a 250 micron        sieve.

Residual Opadry II dispersion is removed from the spray nozzle byrapidly flushing through with the 10% w/w dispersion of Sureteric. Theprecision coater module is washed and then dried by heating at 85° C.for 15 minutes with a nominal airflow of 6.0 m³/Hr. The Opadry II coatedgranules are placed into the precision coater and are fluidised usingthe same conditions as for the addition of Opadry II. Once the materialis equilibrated within the vessel, a constant temperature is reachedwithin the powder bed. At this point the granules are coated with the10% w/w dispersion of Sureteric at a rate of 1.0 g/min. Once a 10-20%wt. gain coating is applied, spraying of the Sureteric dispersion isstopped and the material dried until a constant temperature is observedwithin the powder bed. At this point the airflow temperature is reducedto 25° C. and the bulk material removed, allowing it to cool.

Step 4: Overcoating With Aquacoat CPD

A 20% w/w dispersion of Aquacoat CPD is prepared as follows:

-   -   The necessary quantities of water, Aquacoat CPD and plasticiser        (in this case 24% w/w diethyl phthalate) are accurately weighed        out.    -   With the propeller in the centre and as close to the bottom of        the vessel as possible, the diethyl phthalate is steadily added        to the Aquacoat CPD and mixed for 30 minutes.    -   The water is then slowly added to the mixture and stirred for a        further 10 minutes.

Residual Sureteric dispersion is removed from the spray nozzle byrapidly flushing through with the 20% w/w dispersion of Aquacoat CPD.The precision coater module is washed and then dried by heating at 85°C. for 15 minutes with a nominal airflow of 6.0 m³/Hr. Theenteric-coated granules are placed into the precision coater and arefluidised using the same conditions as for the addition of Eudragit.Once the material is equilibrated within the vessel, a constanttemperature is reached within the powder bed. At this point the granulesare coated with the 20% w/w dispersion of Aquacoat CPD at a rate of 1.5g/min. Once a coating of 4-30% wt. gain is applied spraying of theAquacoat CPD dispersion is stopped and the material dried until aconstant temperature is observed within the powder bed. At this pointthe airflow temperature is reduced to 25° C. and the bulk materialremoved, allowing it to cool.

EXAMPLE 5 Taste-Masked Acetaminophen

Step 1: Granulation of Acetaminophen

Prior to commencing granulation of the Acetaminophen, the vessel of theMP Micro is pre-warmed by heating at 70° C. for 15 minutes with anominal airflow of 6.0 m³/Hr. 76 g of Acetaminophen and 4 g of PVP K-30is added to the vessel and the process temperature set to 70° C. Theairflow is then increased until the product is fluidised. Once aconstant temperature is achieved within the powder bed, spraygranulation of the product is commenced by the introduction of distilledwater as the granulation fluid. An atomising pressure of 2 bar is used.

Once the material is granulated the addition of the granulation fluid isstopped and the powder bulk is dried. The end point of the dryingprocess is indicated by a constant temperature within the powder bed. Atthis point the temperature of the inlet air is reduced to 25° C. and thebulk material removed. Once cooled the material is screened through a250 micron sieve and then air jet sieved to remove particles below 100microns.

Step 2: Spray Coating With Surelease

An aqueous dispersion of Surelease is prepared by diluting to 15% w/wsolids (i.e. 60% Surelease dispersion and 40% distilled or deionisedwater) and stirred using a low shear mixer for approximately 15 minutes.With the precision coater module attached the vessel is preheated at 70°C. for 15 minutes with a nominal airflow of 6.0 m³/Hr. 60 g of thegranulated Acetaminophen is returned to the MP Micro and the processtemperature set at 70° C. to achieve a product temperature of 40-45° C.The airflow is increased until the product is fluidised. Once thematerial is equilibrated within the vessel, a constant temperature isreached within the powder bed. The material is then sprayed with theSurelease dispersion to achieve approximately a 15 to 30% wt. gaindepending on the degree of tastemasking which is required at a sprayingrate of 1.0 g/min with an atomising air pressure of 2 bar.

Once the desired weight of Surelease coating is added to the granules,the pump and the atomising air are stopped and the material is drieduntil the powder bed reaches a constant temperature. At this point theinlet air temperature is reduced to 25° C. and the operation stopped.

Step 3: Overcoating With a Polyvinylalcohol (PVA) Based Coating System

A 10% w/w dispersion of the PVA based coating system is prepared asfollows:

-   -   The necessary quantity of the PVA film coating system is        accurately weighed out.    -   The necessary quantity of water is accurately weighed into the        mixing vessel.    -   With the propeller in the centre and as close to the bottom of        the vessel as possible, the water is stirred to form a vortex        without drawing air into the liquid.    -   The PVA film coating system is steadily added to the vortex,        avoiding powder flotation on the liquid surface.    -   The stirrer speed is increased in order to maintain the vortex        as required.    -   After all the PVA film coating system is added, the mixer speed        is reduced to nearly eliminate the vortex. The dispersion is        then mixed for a further 45 minutes.

Residual Surelease is removed from the spray nozzle by rapidly flushingthrough with the 10% w/w dispersion of the PVA film coating system. Theprecision coater module is washed and then dried by heating at 85° C.for 15 minutes with a nominal airflow of 6.0 m³/Hr. The Surelease coatedgranules are placed into the precision coater and are fluidised usingthe same conditions as for the addition of Surelease. Once the materialis equilibrated within the vessel, a constant temperature is reachedwithin the powder bed. At this point the granules are coated with the10% w/w dispersion of the PVA film coating system at a rate of 1.0g/min. Once a coating of 4-30% wt. gain is applied spraying of the PVAfilm coating system is stopped and the material dried until a constanttemperature is observed within the powder bed. At this point the airflowtemperature is reduced to 25° C. and the bulk material removed, allowingit to cool.

EXAMPLE 6 Taste-Masked Verapamil Hydrochloride

Step 1: Granulation of Verapamil

Prior to commencing granulation of the Verapamil, the vessel of the MPMicro is pre-warmed by heating at 70° C. for 15 minutes with a nominalairflow of 6.0 m³/Hr. 76 g of Verapamil and 4 g of PVP K-30 is added tothe vessel and the process temperature set to 70° C. The airflow is thenincreased until the product is fluidised. Once a constant temperature isachieved within the powder bed, spray granulation of the product iscommenced by the introduction of distilled water as the granulationfluid. An atomising pressure of 2 bar is used.

Once the material is granulated, the addition of the granulation fluidis stopped and the powder bulk is dried. The end point of the dryingprocess is indicated by a constant temperature within the powder bed. Atthis point the temperature of the inlet air is reduced to 25° C. and thebulk material removed. Once cooled the material is screened through a250 micron sieve then air jet sieved to remove particles below 100microns.

Step 2: Spray Coating With Eudragit RD-100

An aqueous dispersion of Eudragit RD-100 is prepared as follows:

-   -   The necessary quantity of Eudragit RD-100 to prepare a 13% w/w        dispersion is accurately weighed out.    -   The necessary quantity of water is accurately weighed into the        mixing vessel and 0.003% w/w polysorbate 80 added to it as a        plasticiser.    -   With the propeller in the centre and as close to the bottom of        the vessel as possible, the water is stirred to form a vortex        without drawing air into the liquid.    -   The Eudragit RD-100 powder is steadily added to the vortex,        avoiding powder flotation on the liquid surface.    -   The stirrer speed is increased in order to maintain the vortex        as required.    -   Once all of the Eudragit is added, the mixer speed is reduced to        nearly eliminate the vortex. The dispersion is then mixed for a        further 30 minutes.    -   The dispersion is then screened through a 0.4 mm mesh prior to        use.

With the precision coater module attached the vessel is preheated at 70°C. for 15 minutes with a nominal airflow of 6.0 m³/Hr. 60 g of thegranulated Verapamil is returned to the MP Micro and the processtemperature set at 95° C. The airflow is increased until the product isfluidised. Once the material is equilibrated within the vessel, aconstant temperature is reached within the powder bed. The material isthen sprayed with the Eudragit RD-100 dispersion to achieveapproximately a 10-15% wt. gain depending on the degree of tastemaskingwhich is required at a spraying rate of 1.0 g/min with an atomising airpressure of 2 bar.

Once the desired weight of Eudragit RD-100 is added to the granules, thepump and the atomising air are stopped and the material dried until thepowder bed reaches a constant temperature. At this point the inlet airtemperature is reduced to 25° C. and the operation stopped.

Step 3: Overcoating With Neutralised Carbopol 971

A 0.5% w/w aqueous dispersion of neutralised Carbopol 971 is prepared asfollows

-   -   The necessary quantity of Carbopol 971 to prepare a 0.5% aqueous        dispersion is accurately weighed out.    -   A 0.0025M dispersion of hydrochloric acid is prepared and the        necessary quantity weighed into the mixing vessel.    -   With the propeller in the centre and as close to the bottom of        the vessel as possible, the 0.0025M dispersion of hydrochloric        acid is stirred to form a vortex without drawing air into the        liquid.    -   The Carbopol 971 powder is steadily added to the vortex,        avoiding powder flotation on the liquid surface.    -   The stirrer speed is increased in order to maintain the vortex        as required.    -   Once all of the Carbopol 971 is added dispersion is mixed for a        further 15-20 minutes or until the polymer is swelled to produce        a smooth product.

Residual Eudragit RD-100 is removed from the spray nozzle by rapidlyflushing through with the dispersion of neutralised Carbopol 971. Theprecision coater module is washed and then dried by heating at 85° C.for 15 minutes with a nominal airflow of 6.0 m³/Hr. The tastemaskedgranules are placed into the precision coater and are fluidised usingthe same conditions as for the addition of Eudragit RD-100. Once thematerial is equilibrated within the vessel, a constant temperature isreached within the powder bed. At this point the granules are coatedwith the 0.5% w/w dispersion of neutralised Carbopol 971 at a rate of 10g/min. Once a coating of 5-30% wt. gain is applied, spraying of theneutralised Carbopol 971 dispersion is stopped and the material drieduntil a constant temperature is observed within the powder bed. At thispoint the airflow temperature is reduced to 25° C. and the bulk materialremoved, allowing it to cool.

EXAMPLE 7 Taste-Masked Amoxycillin

Step 1: Granulation of Amoxycillin

Prior to commencing granulation of the Amoxycillin, the vessel of the MpMicro is pre-warmed by heating at 70° C. for 15 minutes with a nominalairflow of 6.0 m³/Hr. 76 g of Amoxycillin and 4 g of PVP K-30 is addedto the vessel and the process temperature set to 50° C. The airflow isthen increased until the product is fluidised. Once a constanttemperature is achieved within the powder bed, spray granulation of theproduct is commenced by the introduction of 96% ethanol as thegranulation fluid. An atomising pressure of 2 bar is used.

Once the material is granulated the addition of the granulation fluid isstopped and the powder bulk is dried. The end point of the dryingprocess is indicated by a constant temperature within the powder bed. Atthis point the temperature of the inlet air is reduced to 25° C. and thebulk material removed. Once cooled, the material is screened through a250 micron sieve and air jet sieved to remove particles below 100microns.

Step 2: Spray Coating With Opadry AMB

Due to the moisture sensitivity of the Amoxycillin granulation, amoisture barrier film is applied to the material to a 5-30% wt. gainwith a 20% w/w dispersion of Opadry AMB, which is prepared as follows:

-   -   The necessary quantity of Opadry AMB is accurately weighed out.    -   The necessary quantity of water is accurately weighed into the        mixing vessel.    -   With the propeller in the centre and as close to the bottom of        the vessel as possible, the water is stirred to form a vortex        without drawing air into the liquid.    -   The Opadry AMB powder is steadily added to the vortex, avoiding        powder flotation on the liquid surface.    -   The stirrer speed is increased in order to maintain the vortex        as required.    -   After all the Opadry AMB system is added, the mixer speed is        reduced to nearly eliminate the vortex. The dispersion is then        mixed for a further 45 minutes.

With the precision coater module attached the vessel is preheated at 70°C. for 15 minutes with a nominal airflow of 6.0 m³/Hr. 60 g of thegranulated Amoxycillin is returned to the MP Micro and the processtemperature set at 70° C. to achieve a product temperature of 40-45° C.The airflow is increased until the product is fluidised. Once thematerial equilibrated within the vessel, a constant temperature isreached within the powder bed. The 20% w/w dispersion is then sprayedonto the Amoxycillin granules at a rate of 1.0 g/min with an atomisingair pressure of 2.5 bar. Once the desired weight of Opadry AMB isapplied to the granules, the pump and the atomising air are stopped andthe material dried until the powder bed reaches a constant temperature.At this point the inlet air temperature is reduced to 25° C. and theoperation stopped. Once the moisture barrier coating is applied to thegranules it is possible to add the functional tastemasking coat to theAmoxycillin.

Step 2: Overcoating With Surelease

An aqueous dispersion of Surelease is prepared by diluting to 15% w/wsolids (i.e. 60% Surelease dispersion and 40% distilled or deionisedwater) and stirred using a low shear mixer for approximately 15 minutes.With the precision coater module attached the vessel is preheated at 70°C. for 15 minutes with a nominal airflow of 6.0 m³/Hr. 60 g of thegranulated Amoxycillin is returned to the MP Micro and the processtemperature set at 70° C. to achieve a product temperature of 40-45° C.The airflow is increased until the product is fluidised. Once thematerial is equilibrated within the vessel, a constant temperature isreached within the powder bed. The material is then sprayed with theSurelease dispersion to achieve approximately a 15-30% wt. gaindepending on the degree of tastemasking which is required at a sprayingrate of 11.0 g/min with an atomising air pressure of 2 bar.

Once the desired weight of Surelease coating is added to the granulesthe pump and the atomising air are stopped and the material dried untilthe powder bed reaches a constant temperature. At this point the inletair temperature is reduced to 25° C. and the operation stopped.

EXAMPLE 8 Enteric-Coated Mesalazine

Step 1: Granulation of Mesalazine

Prior to commencing granulation of the Mesalazine, the vessel of the MPMicro is pre-warmed by heating at 70° C. for 15 minutes with a nominalairflow of 6.0 m³/Hr. 76 g of Mesalazine and 4 g of PVP K-30 is added tothe vessel and the process temperature set to 70° C. The airflow is thenincreased until the product is fluidised. Once a constant temperature isachieved within the powder bed, spray granulation of the product iscommenced by the introduction of distilled water as the granulationfluid. An atomising pressure of 2 bar is used.

Once the material is granulated, the addition of the granulation fluidis stopped and the powder bulk is dried. The end point of the dryingprocess is indicated by a constant temperature within the powder bed. Atthis point the temperature of the inlet air is reduced to 25° C. and thebulk material removed. Once cooled the material is screened through a250 micron sieve and air jet sieved to remove particles below 100microns.

Step 2: Spray-Coating With Aquacoat CPD

A 20% w/w dispersion of Aquacoat CPD is prepared as follows:

-   -   The necessary quantities of water, Aquacoat CPD and plasticiser        (in this case 24% w/w diethyl phthalate) are accurately weighed        out.    -   With the propeller in the centre and as close to the bottom of        the vessel as possible, the diethyl phthalate is steadily added        to the Aquacoat CPD and mixed for 30 minutes.    -   The water is then slowly added to the mixture and stirred for a        further 10 minutes.

With the precision coater module attached the vessel is preheated at 70°C. for 15 minutes with a nominal airflow of 6.0 m³/Hr. 60 g of thegranulated Mesalazine is returned to the Mp Micro and the processtemperature set at 70° C. to achieve a product temperature of 40-45° C.The airflow is increased until the product is fluidised. Once thematerial equilibrated within the vessel, a constant temperature isreached within the powder bed. The 20% w/w dispersion is then sprayedonto the Mesalazine granules at a rate of 1.0 g/min with an atomisingair pressure of 2.0 bar. Once the desired weight of Aquacoat CPD isapplied to the granules, the pump and the atomising air are stopped andthe material dried until the powder bed reaches a constant temperature.At this point the inlet air temperature is reduced to 25° C. and theoperation stopped.

Step 3: Overcoating With Xanthan Gum

A 5% w/w dispersion of Xanthan Gum is prepared as follows:

-   -   The necessary quantity of Xanthan Gum is accurately weighed out.    -   The necessary quantity of water is accurately weighed into the        mixing vessel.    -   With the propeller in the centre and as close to the bottom of        the vessel as possible, the water is stirred to form a vortex        without drawing air into the liquid.    -   The Xanthan Gum powder is steadily added to the vortex, avoiding        powder flotation on the liquid surface.    -   The stirrer speed is increased in order to maintain the vortex        as required.    -   After all the Xanthan Gum system is added, the mixer speed is        reduced to nearly eliminate the vortex. The dispersion is then        mixed for a further 45 minutes.

Residual Aquacoat CPD is removed from the spray nozzle by rapidlyflushing through with the 5% w/w dispersion of Xanthan Gum. Theprecision coater module is washed and then dried by heating at 85° C.for 15 minutes with a nominal airflow of 6.0 m³/Hr. The enteric coatedgranules are placed into the precision coater and are fluidised usingthe same conditions as for the addition of Aquacoat CPD dispersion. Oncethe material is equilibrated within the vessel, a constant temperatureis reached within the powder bed. At this point the granules are coatedwith the 5% w/w dispersion of Xanthan Gum at a rate of 1.0 g/min. Once acoating of 5-30% wt. gain is applied, spraying of the Xanthan gumdispersion is stopped and the material dried until a constanttemperature is observed within the powderbed. At this point the airflowtemperature is reduced to 25° C. and the bulk material removed, allowingit to cool.

EXAMPLE 9 Controlled-Release Sodium Valproate

Step 1: Granulation of Sodium Valproate

Prior to commencing granulation of the Sodium Valproate, the vessel ofthe MP Micro is pre-warmed by heating at 70° C. for 15 minutes with anominal airflow of 6.0 m³/Hr. 76 g of Sodium Valproate and 4 g of PVPK-30 is added to the vessel and the process temperature set to 70° C.The airflow is then increased until the product is fluidised. Once aconstant temperature is achieved within the powder bed, spraygranulation of the product is commenced by the introduction of distilledwater as the granulation fluid. An atomising pressure of 2 bar is used.Once the material is granulated the addition of the granulation fluid isstopped and the powder bulk is dried. The end point of the dryingprocess is indicated by a constant temperature within the powder bed. Atthis point the temperature of the inlet air is reduced to 25° C. and thebulk material removed. Once cooled the material is screened through a250 micron sieve and air jet sieved to remove particles below 100microns.

Step 2: Spray Coating With Surelease

An aqueous dispersion of Surelease is prepared by diluting to 15% w/wsolids (i.e. 60% Surelease dispersion and 40% distilled or deionisedwater) and stirred using a low shear mixer for approximately 15 minutes.With the precision coater module attached the vessel is preheated at 70°C. for 15 minutes with a nominal airflow of 6.0 m³/Hr. 60 g of thegranulated Sodium Valproate is returned to the MP Micro and the processtemperature set at 70° C. to achieve a product temperature of 40-45° C.The airflow is increased until the product is fluidised. Once thematerial is equilibrated within the vessel, a constant temperature isreached within the powder bed. The material is then sprayed with theSurelease dispersion to achieve a 6-30% wt. gain depending on thedesired release profile at a spraying rate of 1.0 g/min with anatomising air pressure of 2 bar.

Once the desired weight of Surelease coating is added to the granulesthe pump and the atomising air are stopped and the material dried untilthe powder bed reached a constant temperature. At this point the inletair temperature is reduced to 25° C. and the operation stopped.

Stage 3: Overcoating With Eudragit L30 D-55

A plasticized 50% w/w dispersion of Eudragit L30 D-55 formulation forspray coating the Sodium Valproate granules is prepared by diluting to25% w/w solids with between 5 and 15% w/w plasticizer, 0.2% antifoamagent in distilled or deionised water. The dispersion is then stirredusing a low shear mixer for approximately 15 minutes. Prior to use, theplasticized dispersion is filtered through a 0.25 mm sieve. With theprecision coater module attached, the vessel is preheated at 70° C. for15 minutes with a nominal airflow of 6.0 m³/Hr. 60 g of the granulatedSodium Valproate is returned to the MP Micro and the process temperatureset at 95° C. The airflow is increased until the product is fluidised.Once the material is equilibrated within the vessel, a constanttemperature is reached within the powder bed. The material is thensprayed with the Eudragit dispersion (which is continuously stirredthroughout the spraying procedure) to achieve a 8-25% wt. gain dependingon the desired degree of mechanical protection which is required at aspraying rate of 1.0 g/min with an atomising air pressure of 2 bar.

Once the desired weight of Eudragit L30 D-55 coating is added to thegranules, the pump and the atomising air are stopped and the materialdried until the powder bed reached a constant temperature. At this pointthe inlet air temperature is reduced to 25° C. and the operationstopped.

EXAMPLE 10 Wet-Granulated Indomethacin

Step 1: Granulation of Indomethacin

Prior to commencing granulation of the Indomethacin (pulverized), thevessel of an MP Micro fluid bed dryer (available from Niro PharmaSystems of GEA Niro, Inc.) is pre-warmed by heating at 70° C. for 15minutes with a nominal airflow of 6.0 m³/Hr. 96 g of Indomethacin and 4g of PVP K-30 is added to the vessel and the process temperature set to70° C. The airflow is then increased until the product is fluidised.Once a constant temperature is achieved within the powder bed, spraygranulation of the product is commenced by the introduction of distilledwater as the granulation fluid. An atomising pressure of 2 bar is used.

Once the material was granulated, the addition of the granulation fluidwas stopped and the powder bulk was dried. The end point of the dryingprocess is indicated by a constant temperature within the powder bed. Atthis point the temperature of the inlet air is reduced to 25° C. and thebulk material removed. Once cooled, the material was screened through a600 micron sieve.

Dissolution testing was then performed using a United StatesPharmacopeia Type IV dissolution apparatus (hereinafter USP Type IVapparatus), configured to recirculate the dissolution media. Morespecifically, the apparatus was a Sotax CE 70. A flow rate of 32 ml/minwas used. The drug release was quantified by UV absorbance measured at318 nm. Dissolution studies were performed in a basic dissolution media(45 minutes pH 6.8 Phosphate Buffer (3:1 ratio of 0.1N HCl:0.2M Na₃PO₄).

FIG. 3 is a graph plotting the dissolution data for the wet-granulatedIndomethacin and 4% PVP K-30 with the pH 6.8 phosphate buffer. Thecorresponding data plotted in this Figure is shown in the followingtable: TABLE 1 % Dissolved Time (min) Cell 1 Cell 2 Cell 3 0 0 0 0 134.46 42.04 41.12 3 61.21 64.43 64.7 5 75.16 76.27 77.04 10 89.9 90.2390.04 15 95.55 96.55 95.01 20 98.62 100.27 97.6 25 100.45 102.71 99.2830 101.84 104.47 100.46 35 102.86 105.95 101.44 40 103.65 106.94 102.2245 104.36 107.73 102.97

EXAMPLE 11

Enteric Coated Melt Granulated Indomethacin Formulation

Step 1: Melt Granulation of Indomethacin

Using a Mixer-Granulator P1-6 (available from Dionsa Dierks & SoehneGmbH) equipped with a 1 litre jacketed bowl, 180 g of indomethacin(pulverized) was equilibrated at 70° C. for 10 minutes at a mixer speedof 600 rpm. 20 g of powdered polyethylene glycol (PEG) 6000 was added tothe bowl. The massing time, impeller and chopper speeds were varied toachieve to the required granule size distribution (in this case, 100-400microns in diameter). Once granulated, the material was cooled byreducing the temperature of the bowl jacket to 25° C. whilst mixing at aspeed of 100 rpm and a chopper speed of 50 rpm. The mixing continueduntil the temperature of the powder bed stabilized to around thetemperature of the jacketed bowl.

Dissolution testing was then performed using the USP Type IV apparatusdescribed above in connection with Example 10. A flow rate of 32 ml/minwas used. The drug release was quantified by UV absorbance measured at318 nm. Dissolution studies were performed in basic dissolution media(45 minutes pH 6.8 Phosphate Buffer (3:1 ratio of 0.1N HCl:0.2M Na₃PO₄).

FIG. 4 depicts a graph plotting the dissolution data for theIndomethacin and 10% PEG6000 melt granulation with the pH 6.8 phosphatebuffer medium. The corresponding data plotted in this Figure is shown inthe following table: TABLE 2 % Dissolved Time (min) Cell 1 Cell 2 Cell 30 0 0 0 1 55.91 65.8 63.39 3 77.02 83.75 80.46 5 87.97 92.47 89.44 10100.51 101.72 99.24 15 106.07 105.08 103.08 20 108.96 106.8 104.98 25110.37 107.91 106.28 30 112.07 108.71 107.53 35 113.14 109.35 108.32 40113.96 109.96 108.91 45 114.64 110.39 109.44It is evident from this data that melt granulating the Indomethacin withPEG 6000 aids the wetting, and hence, the dissolution of theIndomethacin. Specifically, the melt granulated formulation of Example11 has consistently faster dissolution than the wet granulatedformulation of Example 10.Step 2: Acryl-Eze Enteric Coating of Melt-Granulated Indomethacin andPEG 6000

An aqueous dispersion containing 20% (w/w) Acryl-eze (available fromColorcon) and 0.5% (w/w) simethicone was prepared in an amountsufficient to apply a 15% weight gain of Acryl-eze solids to theindomethacin melt granulation of step 1. The MP-Micro fluid bed drierwas used with a Precision Coater Module attached. The Precision CoaterModule was preheated at 70° C. for 15 minutes with a nominal airflow of6.0 m³/Hr. Approximately 100 g of the melt granulated indomethacin ofstep 1 was loaded into the Precision Coater Module and heated at 60° C.at an airflow sufficient to fluidise the melt granulated indomethacin(hereinafter, the “product”). Once a product temperature of 20°-35° C.was achieved, the product was sprayed with the dispersion of Acryl-eze,until a 15% weight gain was achieved. At this point, the pump andatomising air was stopped, and the sprayed product was dried until theproduct temperature begins to increase. The inlet air temperature wasthen reduced to 25° C. and the drying operation was stopped. Anymaterial which had a diameter greater than 600 microns was removed bysieving.

Dissolution testing was then performed using the USP Type IV apparatusdescribed above in connection with Example 10. A flow rate of 32 ml/minwas used. The drug release was quantified by UV absorbance measured at318 nm. Dissolution studies were performed in both acidic dissolutionmedia (0.1N Hydrochloric Acid for 2 hours) and basic dissolution media(45 minutes pH 6.8 Phosphate Buffer (3:1 ratio of 0.1N HCl:0.2M Na₃PO₄).

A concern before preparing an enteric coated, melt granulatedformulation was that the acid phase drug release would be unacceptablyhigh, due to a mixing of the enteric coating polymer with the PEG 6000melt binder. It was postulated that if this occurred, there would be ahigh degree of drug release in the acid phase due to a dilution of thepolymer coat. To prevent this, a melt binder was selected that showed anappreciable difference in melting point (which, for PEG 6000, is 60-65°C.) from the film forming temperature (which, for Acryl-eze, is 25-35°C.) of the enteric coat polymer. It was believed that the mixing of thetwo materials would thereby be minimised.

FIG. 5 is a graph plotting the dissolution data for Indomethacin & 10%PEG6000 & 15% Acryl-eze melt granulation prepared in Step 2 with the0.1N Hydrochloric Acid medium. The corresponding data plotted in thisFigure is shown in the following table: TABLE 3 % Dissolved Time (min)Cell 1 Cell 2 Cell 3 Cell 4 Cell 5 Cell 6 0 0 0 0 0 0 0 30 0.9 0.31 0.390.47 0.17 0.36 60 1.04 0.35 0.45 0.54 0.2 0.43 90 1.31 0.39 0.49 0.570.25 0.49 120 1.49 0.41 0.53 0.62 0.29 0.53It is evident from this data that the enteric coated melt granulatedIndomethacin formulation of step 2 does not exhibit a high degree ofdrug release in the acid phase. To the contrary, less than 1.5% of theformulation dissolved after 2 hours. As such, this formulation meets theU.S.P. acceptance criteria for “Acid Stage” release of “Delayed-release(Enteric-coated) Articles” (less than 10% released in 2 hours in 0.1 Nhydrochloric acid in each of 6 units (U.S.P. Level A1)).

FIG. 6 is a plot of the dissolution data for the Indomethacin & 10%PEG6000 & 15% Acryleze melt granulation from Step 2 with a pH 6.8phosphate buffer. The corresponding data plotted in this Figure is shownin the following table: TABLE 4 % Dissolved Time (min) Cell 1 Cell 2Cell 3 Cell 4 Cell 5 Cell 6 0 0 0 0 0 0 0 1 4.97 3.87 3.64 8 7.85 8.16 315.54 12.34 11.68 19.13 16.04 17.43 5 25.49 20.08 21.91 31.1 24.63 26.7310 48.14 37.55 42.88 52.55 40.93 44.06 15 64.99 51.69 54.43 65.13 52.1256.24 20 75.34 60.83 62.12 72.9 61.78 65.1 25 81.23 66.99 67.36 77.5569.09 71.12 30 84.62 70.83 71.53 80.95 74.95 75.38 35 86.89 73.62 74.5283.31 79.1 78.37 40 88.54 75.98 77.06 85.09 82.18 80.62 45 89.67 78.1979.2 86.58 84.48 82.3As illustrated in FIG. 6 and Table 4, 78-90% of the indomethacin wasreleased within 45 minutes. As such, this formulation would also appearlikely to meet the U.S.P. “Buffer Stage” release of “Delayed-release(Enteric-coated) Articles”. It should be noted that the data does not,in fact pass the Level B1 U.S.P. criteria (80% released within 45minutes in 6.8 pH buffer in each of 6 units) However, it is believedthat the formulation would likely meet the Level B2 U.S.P. criteria(average release at 45 minutes in 6.8 pH buffer for 12 units is at least75%, with none of the 12 units releasing less than 60% in 45 minutes)and the Level B3 U.S.P. criteria (average release at 45 minutes in 6.8pH buffer for 24 units is at least 75%, with none of the 24 unitsreleasing less than 50% in 45 minutes, and no more than two of the 24units releasing less than 60% in 45 minutes). It should be noted thatthe pH 6.8 buffer phase drug release for this formulation is faster thanthe corresponding pH 6.8 buffer release in the formulations of Examples12-15.

EXAMPLE 12 Melt-Granulated Sureteric Coated Indomethacin Formulation

Step 1: Sureteric Coating of Indomethacin

An aqueous dispersion containing 15% (w/w) Sureteric (available fromColorcon) and 0.33% (w/w) simethicone was prepared in an amountsufficient to apply a 15% weight gain of Sureteric solids to 100 gramsof indomethacin. The MP-Micro fluid bed drier with the Precision CoaterModule attached was used. The Precision Coater Module was preheated at70° C. for 15 minutes with a nominal airflow of 6.0 m³/Hr. Theindomethacin (pulverized) was loaded into the Precision Coater Moduleand heated at 60° C. at an airflow sufficient to fluidise theindomethacin (hereinafter, the “product”). Once a product temperature of40-45° C. was achieved, the product was sprayed with the dispersion ofSureteric, until a 15% weight gain was achieved. At this point, the pumpand atomising air was stopped, and the sprayed product was dried untilthe product temperature begins to increase. The inlet air temperaturewas then reduced to 25° C. and the drying operation was stopped. Anymaterial having a diameter greater than 600 microns was removed bysieving.

Step 2 Melt Granulation

Using the Diosna Mixer-Granulator P1-6 equipped with a 1 litre jacketedbowl, 100 g of the material of step 1 was equilibrated at 70° C. for 10minutes at a mixer speed of 600 rpm. 20 g of powdered polyethyleneglycol (PEG) 6000 was added to the bowl. The massing time, impeller andchopper speeds were varied to achieve the required granule sizedistribution (in this case, 100-400 microns in diameter). Oncegranulated, the material was cooled by reducing the temperature of thebowl jacket to 25° C. whilst mixing at a speed of 100 rpm and a chopperspeed of 50 rpm. The mixing continued until the temperature of thepowder bed stabilized to around the temperature of the jacketed bowl.

Dissolution testing was then performed using the USP Type IV apparatusdescribed above in connection with Example 10. A flow rate of 32 ml/minwas used. The drug release was quantified by UV absorbance measured at318 nm. Dissolution studies were performed in both acidic dissolutionmedia (0.1N Hydrochloric Acid for 2 hours) and basic dissolution media(45 minutes pH 6.8 Phosphate Buffer (3:1 ratio of 0.1N HCl: 0.2MNa₃PO₄).

FIG. 7 is a plot of the the dissolution data of the Melt-granulatedSureteric Coated Indomethacin Formulation (Indomethacin and 15%Sureteric and 10% PEG6000) in 0.1 N Hydrochloric acid. The correspondingdata plotted in this Figure is shown in the following table: TABLE 5 %Dissolved Time (min) Cell 1 Cell 2 Cell 3 Cell 4 Cell 5 Cell 6 0 0 0 0 00 0 30 3.18 3.74 4.47 4.14 4.04 2.58 60 4.75 5.41 6.49 5.8 6 4.13 905.81 6.52 7.65 6.84 7.03 5.05 120 6.57 7.31 8.37 7.59 7.64 5.76It is evident from the acid phase release shown in FIG. 7 and Table 5that Sureteric-coated indomethacin can be melt granulated with PEG6000without adversely affecting the integrity of the polymer coat. Moreover,the formulation meets the U.S.P. acceptance criteria for “Acid Stage”release of “Delayed-release (Enteric-coated) Articles” (Level A1: lessthan 10% released in 2 hours in 0.1 N hydrochloric acid in each of 6units)

FIG. 8 is a plot of the the dissolution data of the Melt-granulatedSureteric Coated Indomethacin Formulation (Indomethacin and 15%Sureteric and 10% PEG6000) using a pH 6.8 phosphate buffer. Thecorresponding data plotted in this Figure is shown in the followingtable: TABLE 6 % Dissolved Time (min) Cell 1 Cell 2 Cell 3 Cell 4 Cell 5Cell 6 0 0 0 0 0 0 0 1 13.15 14.8 18.27 18.68 19.35 14.02 3 27.14 27.5932.03 31.92 30.51 23.47 5 35.82 36.15 40.53 40.26 37.8 30.49 10 48.949.8 53.32 53.07 48.2 42.78 15 56.46 57.52 60.46 60.91 53.41 50.6 2061.4 62.35 65.16 66.64 56.42 56.12 25 64.94 65.72 68.46 71.05 58.6260.22 30 67.58 68.18 71.11 74.51 60.48 63.25 35 69.62 70.25 73.2 77.1761.97 65.67 40 71.33 71.78 75.08 79.38 63.24 67.64 45 72.81 73.12 76.7181.28 64.45 69.24

As shown, the total buffer-phase drug release for melt granulatedSureteric-coated indomethacin is slower than the Acryl-eze coated meltgranulated indomethacin of Example 11. In particular, only one of thesix cells reached 80% drug-release in 45 minutes, with an average 45minute release of 72.93%. It is believed that the slow release may beattributed either to the increased payload on the granules or adeleterious affect on the polymer coat due to the melt granulationprocess.

EXAMPLE 13 Indomethacin Wet Granulation With a 15% Sureteric EntericCoat

Step 1: Wet Granulation of Indomethacin

Prior to commencing granulation of the Indomethacin (pulverized), thevessel of the MP Micro was pre-warmed by heating at 70° C. for 15minutes with a nominal airflow of 6.0 m³/Hr. 96 g of Indomethacin and 4g of PVP K-30 was added to the vessel and the process temperature set to70° C. The airflow is then increased until the product is fluidised.Once a constant temperature was achieved within the powder bed, spraygranulation of the product was commenced by the introduction ofdistilled water as the granulation fluid. An atomising pressure of 2 barwas used. Once the material was granulated, the addition of thegranulation fluid was stopped and the powder bulk was dried. The endpoint of the drying process was indicated by a constant temperaturewithin the powder bed. At this point the temperature of the inlet airwas reduced to 25° C. and the bulk material removed. Once cooled, thematerial was screened through a 600 micron sieve.

Step 2: Spray Coating of Wet-Granulated Indomethacin

An aqueous dispersion containing 15% (w/w) Sureteric (available fromColorcon) and 0.33% (w/w) simethicone was prepared in an amountsufficient to apply a 15% weight gain of Sureteric solids to 100 gramsof indomethacin. The MP-Micro fluid bed drier with the Precision CoaterModule attached was used. The Precision Coater Module was preheated at70° C. for 15 minutes with a nominal airflow of 6.0 m3/Hr. Theindomethacin-PVP granulation was loaded into the Precision Coater Moduleand heated at 60° C. at an airflow sufficient to fluidise theindomethacin-PVP granulation (hereinafter, the “product”). Once aproduct temperature of 40-45° C. was achieved, the product was sprayedwith the dispersion of Sureteric, until a 15% weight gain was achieved.At this point, the pump and atomising air was stopped, and the sprayedproduct was dried until the product temperature begins to increase. Theinlet air temperature was then reduced to 25° C. and the dryingoperation was stopped. Any material having a diameter greater than 600microns was removed by sieving.

Dissolution testing was then performed using the USP Type IV apparatusdescribed above in connection with Example 10. A flow rate of 32 ml/minwas used. The drug release was quantified by UV absorbance measured at318 nm. Dissolution studies were performed in both acidic dissolutionmedia (0.1N Hydrochloric Acid for 2 hours) and basic dissolution media(45 minutes pH 6.8 Phosphate Buffer (3:1 ratio of 0.1N HCl:0.2M Na₃PO₄).

FIG. 9 is a plot of the dissolution data of the Indomethacin Granulationwith a 15% Sureteric Enteric Coat (Indomethacin and 15% Sureteric) in0.1 N Hydrochloric acid. The corresponding data plotted in this Figureis shown in the following table: TABLE 7 % Dissolved Time (min) Cell 1Cell 2 Cell 3 Cell 4 Cell 5 Cell 6 0 0 0 0 0 0 0 30 4.67 6.21 7.24 4.284.64 5.48 60 6.53 8.1 7.88 5.93 6.28 7.19 90 7.48 8.93 8.71 6.72 7.17.96 120 8.12 9.38 9.27 7.31 7.58 8.63

As such, this formulation meets the U.S.P. acceptance criteria for “AcidStage” release of “Delayed-release (Enteric-coated) Articles” (less than10% released in 2 hours in 0.1 N hydrochloric acid in each of 6 units(U.S.P. Level A1)).

FIG. 10 is a plot of the the dissolution data of IndomethacinGranulation with a 15% Sureteric Enteric Coat in a pH 6.8 phosphatebuffer. The corresponding data plotted in this Figure is shown in thefollowing table: TABLE 8 % Dissolved Time (min) Cell 1 Cell 2 Cell 3Cell 4 Cell 5 Cell 6 0 0 0 0 0 0 0 1 26.02 29.74 23.48 21.58 42.41 31.793 42.35 46.91 36.02 33.41 50.45 44.38 5 51.39 56.98 43.54 44.72 56.1752.24 7 57.32 63.61 48.53 51.86 60.18 57.39 9 61.46 68.38 52.49 56.6664.53 61.23 11 64.57 71.84 55.65 60.1 66.63 64.04 13 66.93 74.55 58.2162.75 68.89 66.3 15 68.76 76.62 60.46 64.87 70.33 68.06 20 72.11 80.2264.02 68.89 73.78 71.26 25 74.27 82.39 66.3 71.89 75.88 73.36 30 75.8283.88 68.02 74.11 77.35 74.88 35 77.03 85.01 69.09 75.79 78.63 76.06 4078.02 85.97 69.87 77.24 79.67 77.04 45 78.87 86.61 70.41 78.48 80.6877.84

As illustrated by the data in FIG. 10 and Table 8, this formulationwould also appear likely to meet the U.S.P. “Buffer Stage” release of“Delayed-release (Enteric-coated) Articles”. It should be noted that thedata does not, in fact pass the Level B1 U.S.P. criteria (80% releasedwithin 45 minutes in 6.8 pH buffer in each of 6 units) However, it isbelieved that the formulation would likely meet the Level B2 U.S.P.criteria (average release at 45 minutes in 6.8 pH buffer for 12 units isat least 75%, with none of the 12 units releasing less than 60% in 45minutes) and the Level B3 U.S.P. criteria (average release at 45 minutesin 6.8 pH buffer for 24 units is at least 75%, with none of the 24 unitsreleasing less than 50% in 45 minutes, and no more than two of the 24units releasing less than 60% in 45 minutes).

EXAMPLE 14 Sureteric and LustreClear Coated Indomethacin

Steps 1 and 2: Sureteric Coating of Indomethacin

Indomethacin (pulverized) was coated with Sureteric in the same manneras described in steps 1 and 2 of Example 13.

Step 3: Overcoating With LustreClear

An aqueous dispersion containing 9% (w/w) LustreClear (available fromFMC Biopolymer) was prepared in an amount sufficient to apply a 10%weight gain of LustreClear solids to the sureteric coated indomethacinof steps 1 and 2. The MP-Micro fluid bed drier with the Precision CoaterModule attached was used. The Precision Coater Module was preheated at70° C. for 15 minutes with a nominal airflow of 6.0 m³/Hr. The SuretericCoated Indomethacin was loaded into the Precision Coater Module andheated at 60° C. at an airflow sufficient to fluidise the indomethacin(hereinafter, the “product”). Once a product temperature of 40-45° C.was achieved, the product was sprayed with the dispersion ofLustreClear, until a 10% weight gain was achieved. At this point, thepump and atomising air was stopped, and the sprayed product was drieduntil the product temperature began to increase. The inlet airtemperature was then reduced to 25° C. and the drying operation wasstopped. Any material having a diameter greater than 600 microns wasremoved by sieving.

Dissolution testing was then performed using the USP Type IV apparatusdescribed above in connection with Example 10. A flow rate of 32 ml/minwas used. The drug release was quantified by UV absorbance measured at318 nm. Dissolution studies were performed in both acidic dissolutionmedia (0.1N Hydrochloric Acid for 2 hours) and basic dissolution media(45 minutes pH 6.8 Phosphate Buffer (3:1 ratio of 0.1 N HCl:0.2MNa₃PO₄).

FIG. 11 is a plot of the dissolution data for the Indomethacin and 15%Sureteric with 10% LustreClear in 0.1N Hydrochloric Acid. Thecorresponding data plotted in this Figure is shown in the followingtable: TABLE 9 % Dissolved Time (min) Cell 1 Cell 2 Cell 3 Cell 4 Cell 5Cell 6 0 0 0 0 0 0 0 30 2.17 3.22 3.75 3.9 3.01 2.91 60 2.49 4.91 5.395.47 4.15 4.19 90 3.21 5.65 6.14 6.21 4.86 4.89 120 3.94 6.39 6.82 6.985.32 5.36

It should be noted that the acid-phase drug release of FIG. 11 and Table9 shows more variability than in the sureteric coated melt-granulationof Example 12, FIG. 7 and Table 5. This suggests that the coating of thePEG6000 of Example 12 may aid the wetting of the particles and henceresult in a more reproducible dissolution profile in vitro.

FIG. 12 is a plot of the dissolution data for Indomethacin and 15%Sureteric with 10% LustreClear in the pH 6.8 phosphate buffer. Thecorresponding data plotted in this Figure is shown in the followingtable: TABLE 10 % Dissolved Time (min) Cell 1 Cell 2 Cell 3 Cell 4 Cell5 Cell 6 0 0 0 0 0 0 0 1 23.11 30.34 26.24 32.83 31.27 31 3 33.2 40.6537.14 44.71 42.09 40.67 5 38.95 46.5 42.72 50.98 47.86 46.15 7 42.8550.75 46.72 55.45 52.15 50.35 9 45.83 54.12 49.69 58.93 55.53 53.72 1148.12 56.88 52.01 61.69 58.18 55.95 13 50.05 59.09 54 64.05 60.52 58.1515 51.61 60.94 55.58 66.14 62.5 60.07 20 54.69 64.7 58.72 70.38 66.4364.41 25 56.88 67.7 61.01 73.67 69.38 67.24 30 58.48 70.02 62.8 76.3971.62 69.61 35 59.81 71.93 64.28 78.63 73.38 71.19 40 60.93 73.54 65.5580.64 74.86 72.71 45 61.88 75.01 66.7 82.37 76.17 73.88

The buffer-phase dissolution profile for this formulation is slow inthat only one of the six cells reached 80% drug-release in 45 minutes,with an average 45 minute release of 72.67%. This formulation shows asimilar profile to the PEG 6000 melt-granulated, Sureteric-coatedindomethacin of Example 12 and FIG. 8.

EXAMPLE 15 Lab Scale Melt Granulation of Indomethacin and PEG 6000

The formulation was prepared in the same manner as Example 11, step 1,except that the indomethacin (pulverized) and PEG 600 were mixed in abeaker on a hot-plate using an overhead stirrer, rather than in theDiosna Mixer-Granulator P1-6.

EXAMPLE 16

A particle size distribution for the formulations of Examples 10, 11(steps 1 & 2), and Example 11 (Step 1) is shown in FIG. 13. The data wasgenerated by laser diffraction of particles suspended in an airstreamusing a Malvern Mastersizer 2000. Referring to FIG. 13, it is shown thatthe formulation of Example 11 (steps 1 and 2) has the overall largestparticle sizes (almost 100% of particles are at least 60 microns),followed the formulation of Example 11 (step 1, only), followed by theformulation of Example 10.

A Twin Stage Impinger Apparatus (glass with a 12.8 mm jet) was used todetermine the fine particle fraction of the formulations of Examples 10,11 (steps 1 & 2), 11 (step 1 only), 14, and 15, with the followingresults: Average % Fine Particle Fraction Material at 601/min (n = 5) 1)Raw indomethacin (pulverized) 3.89 2) Indomethacin (pulverized) & 4% PVPK-30 0.32    (Example 10) 3) Indomethacin (pulverized) & 10% PEG 60000.14    (Example 15) 4) Indomethacin (pulverized) & 10% PEG 6000 0.04   (Example 11, step 1) 5) Indomethacin (pulverized) & 10% PEG 6000 &0.05    15% Acryl-eze (Example 11, steps 1 and 2) 6) Indomethacin(pulverized) & 15% Sureteric & 0.09    10% LustreClear (Example 14)

This fine particle fraction data is consistent with the particle sizedistribution data of FIG. 13 in that the % Fine Particle Fraction islowest for Example 11 (steps 1 & 2) and highest for Example 10. Example14 exhibited a fine particle fraction which was lower than Example 14,but higher than Example 11. The formulation of Example 15 had a fineparticle fraction which was lower than Example 10, but higher thanExamples 11 and 14. This illustrates that high shear mixing (e.g., withthe Dionsna Mixer-Granulator P1-6) produces denser particles having asmaller fine particle fraction than simple mixing in a beaker with anoverhead stirrer.

1. A drug formulation for gastrointestinal deposition comprising anon-compressed free flowing plurality of particles comprising a corecomprising a drug and a pharmaceutically acceptable excipient, said coreovercoated with a functional coating, said drug particles having a meandiameter of greater than 10 μm to about 1 mm, said particles comprisingat least about 40% drug.
 2. The drug formulation of claim 1 wherein saidcore comprises drug coated with said excipient and said functional coatovercoats the excipient coat.
 3. The drug formulation of claim 1 whereinsaid core comprises a drug interdispersed in said excipient.
 4. Theformulation of claim 3 wherein said drug and said excipient are wetgranulated.
 5. The formulation of claim 3 wherein said drug and saidexcipient are melt granulated.
 6. The formulation of claim 3 whereinsaid drug and a first portion of said excipient are wet granulated andthe resultant wet granulated particles are melt granulated with a secondportion of said excipient.
 7. The formulation of claim 6 wherein saidfirst portion of excipient and said second portion of excipient comprisethe same material.
 8. The formulation of claim 6 wherein said firstportion of excipient and said second portion of excipient comprisedifferent materials.
 9. The formulation of claim 1 wherein saidfunctional coated particles are melt granulated with a pharmaceuticallyacceptable excipient.
 10. The formulation of claim 5 wherein adifference between a film forming temperature of the melt granulatingexcipient and the film forming temperature of the functional coat ismore than 15 degrees C.
 11. The formulation of claim 10 wherein thedifference between a film forming temperature of a melt granulatingexcipient and the film forming temperature of a functional coat is morethan 20 degrees C.
 12. The formulation of claim 11 wherein a differencebetween a film forming temperature of the melt granulating excipient anda film forming temperature of the functional coat is more than 25degrees C.
 13. The formulation of claim 5 wherein the melt granulatingexcipient is selected from the group consisting of beeswax, white wax,emulsifying wax, hydrogenated vegetable oil, cetyl alcohol, stearylalcohol, stearic acid; esters of wax acids; propylene glycolmonostearate, glyceryl monostearate; carnauba wax, glycerylpalmitostearate, glyceryl behenate, polyethylene glycol, and acombination thereof.
 14. The drug formulation of claim 1 wherein saidexcipient provides a controlled release of the drug upongastrointestinal deposition.
 15. The drug formulation of claim 14wherein said excipient provides a controlled release of the drug upongastrointestinal deposition to provide a therapeutic effect for at least12 hours after oral administration.
 16. The drug formulation of claim 14wherein said excipient provides a controlled release of the drug upongastrointestinal deposition to provide a therapeutic effect for at least24 hours after oral administration.
 17. The drug formulation of claim 1wherein said excipient provides a delayed release of the drug upongastrointestinal deposition.
 18. The drug formulation of claim 17wherein said excipient provides a delayed release of the drug upongastrointestinal deposition to effect intestinal absorption.
 19. Thedrug formulation of claim 1 wherein said excipient providestastemasking.
 20. The drug formulation of claim 1 wherein said excipientcomprises a salivary stimulant.
 21. The drug formulation of claim 2wherein said excipient provides a moisture barrier.
 22. The drugformulation of claim 1 wherein said excipient provides a texturemodifier.
 23. The drug formulation of claim 1 wherein said functionalcoating provides a controlled release of the drug upon gastrointestinaldeposition.
 24. The drug formulation of claim 12 wherein said functionalcoating provides a controlled release of the drug upon gastrointestinaldeposition to provide a therapeutic effect for at least 12 hours afteroral administration.
 25. The drug formulation of claim 12 wherein saidfunctional coating provides a controlled release of the drug upongastrointestinal deposition to provide a therapeutic effect for at least24 hours after oral administration.
 26. The drug formulation of claim 1wherein said functional coating provides a delayed release of the drugupon gastrointestinal deposition.
 27. The drug formulation of claim 26wherein said functional coating provides a delayed release of the drugupon gastrointestinal deposition to effect intestinal absorption. 28.The drug formulation of claim 1 wherein said functional coating providestastemasking.
 29. The drug formulation of claim 1 wherein saidfunctional coating comprises a salivary stimulant.
 30. The drugformulation of claim 1 wherein said functional coating provides amoisture barrier.
 31. The drug formulation of claim 1 wherein saidfunctional coating provides a texture modifier.
 32. The drug formulationof claim 1 wherein said functional coating minimizes asperities on thesurface of said particles.
 33. The drug formulation of claim 1 whereinsaid functional coating is resistant to chipping.
 34. The drugformulation of claim 1 wherein said functional coating providespliability to said particles.
 35. The drug formulation of claim 1wherein said drug particles have a mean diameter of greater than about50 μm.
 36. The drug formulation of claim 1 wherein greater than 90% ofsaid particles have a diameter of greater than about 10 μm.
 37. The drugformulation of claim 1 wherein greater than 95% of said particles have adiameter of greater than about 10 μm.
 38. The drug formulation of claim1 wherein greater than 99% of said particles have a diameter of greaterthan about 10 μm.
 39. The drug formulation of claim 1 wherein greaterthan 90% of said particles have a diameter of greater than about 50 μm.40. The drug formulation of claim 1 wherein greater than 95% of saidparticles have a diameter of greater than about 50 μm.
 41. The drugformulation of claim 1 wherein greater than 99% of said particles have adiameter of greater than about 50 μm.
 42. The drug formulation of claim14 wherein said controlled release excipient is a hydrophobic material.43. The drug formulation of claim 42 wherein said hydrophobic materialis selected from the group consisting of an acrylic polymer, acellulosic material, shellac, zein and mixtures thereof.
 44. The drugformulation of claim 42 wherein said hydrophobic material is an acrylicpolymer.
 45. The drug formulation of claim 44 wherein said acrylicpolymer is selected from the group consisting of acrylic acid andmethacrylic acid copolymers, methacrylic acid copolymers, methylmethacrylate copolymers, ethoxyethyl methacrylates, cynaoethylmethacrylate, methyl methacrylate, copolymers, methacrylic acidcopolymers, methyl methacrylate copolymers, methyl methacrylatecopolymers, methyl methacrylate copolymers, methacrylic acid copolymer,aminoalkyl methacrylate copolymer, methacrylic acid copolymers, methylmethacrylate copolymers, poly(acrylic acid), poly(methacrylic acid,methacrylic acid alkylamide copolymer, poly(methyl methacrylate),poly(methacrylic acid) (anhydride), methyl methacrylate,polymethacrylate, methyl methacrylate copolymer, poly(methylmethacrylate), poly(methyl methacrylate) copolymer, polyacrylamide,aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride),glycidyl methacrylate copolymers and mixtures thereof.
 46. The drugformulation of claim 42 wherein said controlled release excipient is acellulosic material.
 47. The drug formulation of claim 46 wherein saidcellulosic material is selected from the group consisting of celluloseesters, cellulose diesters, cellulose triesters, cellulose ethers,cellulose ester-ether, cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, cellulose acetate propionate, cellulose acetate butyrate andmixtures thereof.
 48. The drug formulation of claim 17 wherein saiddelayed release material is an enteric polymer.
 49. The drug formulationof claim 37 wherein said enteric polymer is selected from the groupconsisting of methacrylic acid copolymers, cellulose acetate phthalate,hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcelluloseacetate succinate, polyvinyl acetate phthalate, cellulose acetatetrimellitate, carboxymethylethylcellulose and mixtures thereof.
 50. Thedrug formulation of claim 19 wherein said tastemasking material isselected from the group consisting of water-soluble sweetening agents,water-soluble artificial sweeteners, dipeptide based sweeteners andmixtures thereof.
 51. The drug formulation of claim 50 wherein saidwater-soluble sweetening agent is selected from the group consisting ofmonosaccharides, disaccharides and polysaccharides such as xylose,ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, sugar,maltose, partially hydrolyzed starch, or corn syrup solids and sugaralcohols such as sorbitol, xylitol, or mannitol and mixtures thereof.52. The drug formulation of claim 50 wherein said water-solubleartificial sweetener is selected from the group consisting of solublesaccharin salts, such as sodium or calcium saccharin salts, cyclamatesalts, acesulfam-K, the free acid form of saccharin and mixturesthereof.
 53. The drug formulation of claim 50 wherein said dipeptidebased sweetener is L-aspartyl L-phenylalanine methyl ester.
 54. The drugformulation of claim 20 wherein said salivary stimulant is selected fromthe group consisting of citric acid, tartaric acid, malic acid, fumaricacid, adipic acid, succinic acid, acid anhydrides thereof, acid saltsthereof and combinations thereof.
 55. The drug formulation of claim 21wherein said moisture barrier material is selected from the groupconsisting of acacia gum, acrylic acid polymers and copolymers(polyacrylamides, polyacryldextrans, polyalkyl cyanoacrylates,polymethyl methacrylates), agar-agar, agarose, albumin, alginic acid andalginates, carboxyvinyl polymers, cellulose derivatives such ascellulose acetate, polyamides (nylon 6-10, poly(adipyl-L-lysines,polyterephthalamides and poly-(terephthaloyl-L-lysines)),poly-.epsilon.-caprolactam, polydimethylsiloxane, polyesters,poly(ethylene-vinyl acetate), polyglycolic acid, polyactic acid and itscopolymers, polyglutamic acid, polylysine, polystyrene, shellac, xanthangum, anionic polymers of methacrylic acid and methacrylic acid esters,hydroxyalkylcelluloses and mixtures thereof.
 56. The drug formulation ofclaim 55 wherein said hydroxyalkylcellulose ishydroxypropylmethylcellulose.
 57. The drug formulation of claim 22wherein said texture modifier is selected from the group consisting ofacacia gum, acrylic acid polymers and copolymers (polyacrylamides,polyacryldextrans, polyalkyl cyanoacrylates, polymethyl methacrylates),agar-agar, agarose, albumin, alginic acid and alginates, carboxyvinylpolymers, cellulose derivatives such as cellulose acetate, polyamides(nylon 6-10, poly(adipyl-L-lysines, polyterephthalamides andpoly-(terephthaloyl-L-lysines)), poly-epsilon.-caprolactam,polydimethylsiloxane, polyesters, poly (ethylene-vinyl acetate),polyglycolic acid, polyactic acid and its copolymers, polyglutamic acid,polylysine, polystyrene, shellac, xanthan gum, anionic polymers ofmethacrylic acid and methacrylic acid esters, hydroxyalkylcelluloses andmixtures thereof.
 58. The drug formulation of claim 32 wherein saidparticulates have a mean rugosity of from about 1.0 to about 1.5. 59.The drug formulation of claim 33 wherein said chip resistant coatingcomprises a material selected from the group consisting of acacia gum,alginic acid and alginates, carboxymethylcellulose, ethylcellulose,gelatine, hydroxypropylcellulose, hydroxypropylmethylcellulose,methylcellulose, xanthan gum, pectin, tragacanth, microcrystallinecellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, sodiumcarboxymethylcellulose, polyethylene glycols, polyvinylpyrrolidone,polyvinyl alcohol, polyacrylic acid, gum arabic, lactose, starch (wheat,maize, potato and rice starch), sucrose, glucose, mannitol, sorbitol,xylitol, stearic acid, hydrogenated cottonseed oil, hydrogenated castoroil, vinylpyrrolidone-vinyl acetate copolymers, fructose,methylhydroxyethylcellulose, agar-agar, carrageenan, karaya gum,chitosan, starch hydrolysates and mixtures thereof.
 60. The drugformulation of claim 34 wherein said pliable coating comprises aplasticizer selected from the group consisting of dibutyl sebacate,diethyl phthalate, triethyl citrate, tibutyl citrate, triacetin andmixtures thereof.
 61. A drug delivery system comprising a dosing devicecomprising a housing and an actuator, said device containing at leastone unit dose of a drug formulation according to claim 1, said deviceupon actuation delivering a unit dose of said drug formulation such thatan effective dose of said drug cannot be delivered into the lower lungof a human patient.
 62. A drug delivery system comprising a multipleunit dosing device comprising a housing and an actuator, said devicecontaining multiple unit doses of a drug formulation according to claim1, said device upon actuation delivering a unit dose of said drugformulation such that an effective dose of said drug cannot be deliveredinto the lower lung of a human patient.
 63. A drug delivery systemcomprising a multiple unit dosing device comprising a housing and anactuator, said device containing at least one unit dose of a drugformulation comprising a non-compressed free flowing plurality ofparticles comprising a core comprising a drug and a pharmaceuticallyacceptable excipient, said core overcoated with a functional coating,said drug particles having a mean diameter of greater than 10 μm toabout 1 mm, said device upon actuation delivering a unit dose of saiddrug formulation such that an effective dose of said drug cannot bedelivered into the lower lung of a human patient.
 64. The formulation ofclaim 63 wherein said drug and said excipient are wet granulated. 65.The formulation of claim 63 wherein said drug and said excipient aremelt granulated.
 66. The formulation of claim 63 wherein said drug and afirst portion of said excipient are wet granulated and the resultant wetgranulated particles are melt granulated with a second portion of saidexcipient.
 67. The formulation of claim 66 wherein said first portion ofexcipient and said second portion of excipient comprise the samematerial.
 68. The formulation of claim 66 wherein said first portion ofexcipient and said second portion of excipient comprise differentmaterials.
 69. The formulation of claim 63 wherein said functionalcoated particles are melt granulated with a pharmaceutically acceptableexcipient.
 70. The formulation of claim 65 wherein a difference betweena film forming temperature of the melt granulating excipient and a filmforming temperature of a functional coat is more than 15 degrees C. 71.The formulation of claim 70 wherein a difference between a film formingtemperature of a melt granulating excipient and a film formingtemperature of the functional coat is more than 20 degrees C.
 72. Theformulation of claim 71 wherein a difference between a film formingtemperature point of the melt granulating excipient and a film formingtemperature of the functional coat is more than 25 degrees C.
 73. Theformulation of claim 65 wherein the melt granulating excipient isselected from the group consisting of beeswax, white wax, emulsifyingwax, hydrogenated vegetable oil, cetyl alcohol, stearyl alcohol, stearicacid; esters of wax acids; propylene glycol monostearate, glycerylmonostearate; carnauba wax, glyceryl palmitostearate, glyceryl behenate,polyethylene glycol, and a combination thereof.
 74. A method ofadministering a drug to a human patient for gastrointestinal depositioncomprising formulating a drug formulation comprising a non-compressedfree flowing plurality of particles comprising a core comprising a drugand a pharmaceutically acceptable excipient, said core overcoated with afunctional coating, said drug particles having a mean diameter ofgreater than 10 μm to about 1 mm, containing said drug formulation in adrug delivery device capable of administering multiple unit doses ofsaid multiparticulates into the oral cavity; administering a unit doseof the multiparticulates to the oral cavity wherein greater than about80% of the unit dose is deposited in the gastrointestinal tract.
 75. Amethod of preparing a drug delivery system for delivering multiple dosesof a drug for gastrointestinal deposition comprising preparing a drugformulation comprising a non-compressed free flowing plurality ofparticles comprising a core comprising a drug and a pharmaceuticallyacceptable excipient, said core overcoated with a functional coating,said drug particles having a mean diameter of greater than 10 μm toabout 1 mm; and placing multiple unit doses of said drug formulation ina device which meters a single unit dose for delivery.
 76. The method ofclaim 74 wherein said core comprises drug coated with said excipient andsaid functional coat overcoats the excipient coat.
 77. The method ofclaim 74 wherein said core comprises a drug interdispersed in saidexcipient.
 78. The formulation of claim 77 wherein said drug and saidexcipient are wet granulated.
 79. The formulation of claim 77 whereinsaid drug and said excipient are melt granulated.
 80. The formulation ofclaim 77 wherein said drug and a first portion of said excipient are wetgranulated and the resultant wet granulated particles are meltgranulated with a second portion of said excipient.
 81. The formulationof claim 80 wherein said first portion of excipient and said secondportion of excipient comprise the same material.
 82. The formulation ofclaim 80 wherein said first portion of excipient and said second portionof excipient comprise different materials.
 83. The formulation of claim74 wherein said functional coated particles are melt granulated with apharmaceutically acceptable excipient.
 84. The formulation of claim 79wherein a difference between a film forming temperature of the meltgranulating excipient and a film forming temperature of the functionalcoat is more than 15 degrees C.
 85. The formulation of claim 84 whereina difference between a film forming temperature of the melt granulatingexcipient and a film forming temperature of the functional coat is morethan 20 degrees C.
 86. The formulation of claim 85 wherein a differencebetween a film forming temperature of the melt granulating excipient anda film forming temperature of the functional coat is more than 25degrees C.
 87. The formulation of claim 79 wherein the melt granulatingexcipient is selected from the group consisting of beeswax, white wax,emulsifying wax, hydrogenated vegetable oil, cetyl alcohol, stearylalcohol, stearic acid; esters of wax acids; propylene glycolmonostearate, glyceryl monostearate; carnauba wax, glycerylpalmitostearate, glyceryl behenate, polyethylene glycol, and acombination thereof.
 88. The method of claim 74 wherein said excipientprovides a controlled release of the drug upon gastrointestinaldeposition.
 89. The method of claim 88 wherein said excipient provides acontrolled release of the drug upon gastrointestinal deposition toprovide a therapeutic effect for at least 12 hours after oraladministration.
 90. The method of claim 88 wherein said excipientprovides a controlled release of the drug upon gastrointestinaldeposition to provide a therapeutic effect for at least 24 hours afteroral administration.
 91. The method of claim 74 wherein said excipientprovides a delayed release of the drug upon gastrointestinal deposition.92. The method of claim 91 wherein said excipient provides a delayedrelease of the drug upon gastrointestinal deposition to effectintestinal absorption.
 93. The method of claim 74 wherein said excipientprovides tastemasking.
 94. The method of claim 74 wherein said excipientcomprises a salivary stimulant.
 95. The method of claim 76 wherein saidexcipient provides a moisture barrier.
 96. The method of claim 74wherein said excipient provides a texture modifier.
 97. The method ofclaim 74 wherein said functional coating provides a controlled releaseof the drug upon gastrointestinal deposition.
 98. The method of claim 97wherein said functional coating provides a controlled release of thedrug upon gastrointestinal deposition to provide a therapeutic effectfor at least 12 hours after oral administration.
 99. The method of claim97 wherein said functional coating provides a controlled release of thedrug upon gastrointestinal deposition to provide a therapeutic effectfor at least 24 hours after oral administration.
 100. The method ofclaim 74 wherein said functional coating provides a delayed release ofthe drug upon gastrointestinal deposition.
 101. The method of claim 100wherein said functional coating provides a delayed release of the drugupon gastrointestinal deposition to effect intestinal absorption. 102.The method of claim 74 wherein said functional coating providestastemasking.
 103. The method of claim 74 wherein said functionalcoating comprises a salivary stimulant.
 104. The method of claim 74wherein said functional coating provides a moisture barrier.
 105. Themethod of claim 74 wherein said functional coating provides a texturemodifier.
 106. The method of claim 74 wherein said functional coatingminimizes asperities on the surface of said particles.
 107. The methodof claim 74 wherein said functional coating is resistant to chipping.108. The method of claim 74 wherein said functional coating providespliability to said particles.
 109. The system of claim 74 wherein saiddrug particles have a mean diameter of greater than about 50 μm. 110.The method of claim 74 wherein greater than 90% of said particles have adiameter of greater than about 10 μm.
 111. The method of claim 74wherein greater than 95% of said particles have a diameter of greaterthan about 10 μm.
 112. The method of claim 74 wherein greater than 99%of said particles have a diameter of greater than about 10 μm.
 113. Themethod of claim 74 wherein greater than 90% of said particles have adiameter of greater than about 50 μm.
 114. The method of claim 74wherein greater than 95% of said particles have a diameter of greaterthan about 50 μm.
 115. The method of claim 74 wherein greater than 99%of said particles have a diameter of greater than about 50 μm.
 116. Themethod of claim 88 wherein said controlled release excipient is ahydrophobic material.
 117. The method of claim 116 wherein saidhydrophobic material is selected from the group consisting of an acrylicpolymer, a cellulosic material, shellac, zein and mixtures thereof. 118.The method of claim 116 wherein said hydrophobic material is an acrylicpolymer.
 119. The method of claim 118 wherein said acrylic polymer isselected from the group consisting of acrylic acid and methacrylic acidcopolymers, methacrylic acid copolymers, methyl methacrylate copolymers,ethoxyethyl methacrylates, cynaoethyl methacrylate, methyl methacrylate,copolymers, methacrylic acid copolymers, methyl methacrylate copolymers,methyl methacrylate copolymers, methyl methacrylate copolymers,methacrylic acid copolymer, aminoalkyl methacrylate copolymer,methacrylic acid copolymers, methyl methacrylate copolymers,poly(acrylic acid), poly(methacrylic acid, methacrylic acid alkylamidecopolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), methyl methacrylate, polymethacrylate, methyl methacrylatecopolymer, poly(methyl methacrylate), poly(methyl methacrylate)copolymer, polyacrylamide, aminoalkyl methacrylate copolymer,poly(methacrylic acid anhydride), glycidyl methacrylate copolymers andmixtures thereof.
 120. The method of claim 116 wherein said controlledrelease excipient is a cellulosic material.
 121. The method of claim 120wherein said cellulosic material is selected from the group consistingof cellulose esters, cellulose diesters, cellulose triesters, celluloseethers, cellulose ester-ether, cellulose acylate, cellulose diacylate,cellulose triacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, cellulose acetate propionate, cellulose acetate butyrate andmixtures thereof.
 122. The method of claims 91 and 100 wherein saiddelayed release material is an enteric polymer.
 123. The method of claim122 wherein said enteric polymer is selected from the group consistingof methacrylic acid copolymers, cellulose acetate phthalate,hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcelluloseacetate succinate, polyvinyl acetate phthalate, cellulose acetatetrimellitate, carboxymethylethylcellulose and mixtures thereof.
 124. Themethod of claim 93 wherein said tastemasking material is selected fromthe group consisting of water-soluble sweetening agents, water-solubleartificial sweeteners, dipeptide based sweeteners and mixtures thereof.125. The drug formulation of claim 124 wherein said water-solublesweetening agent is selected from the group consisting ofmonosaccharides, disaccharides and polysaccharides such as xylose,ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, sugar,maltose, partially hydrolyzed starch, or corn syrup solids and sugaralcohols such as sorbitol, xylitol, or mannitol and mixtures thereof.126. The method of claim 124 wherein said water-soluble artificialsweetener is selected from the group consisting of soluble saccharinsalts, such as sodium or calcium saccharin salts, cyclamate salts,acesulfam-K, the free acid form of saccharin and mixtures thereof. 127.The method of claim 124 wherein said dipeptide based sweetener isL-aspartyl L-phenylalanine methyl ester.
 128. The method of claim 94wherein said salivary stimulant is selected from the group consisting ofcitric acid, tartaric acid, malic acid, fumaric acid, adipic acid,succinic acid, acid anhydrides thereof, acid salts thereof andcombinations thereof.
 129. The method of claim 95 wherein said moisturebarrier material is selected from the group consisting of acacia gum,acrylic acid polymers and copolymers (polyacrylamides,polyacryldextrans, polyalkyl cyanoacrylates, polymethyl methacrylates),agar-agar, agarose, albumin, alginic acid and alginates, carboxyvinylpolymers, cellulose derivatives such as cellulose acetate, polyamides(nylon 6-10, poly(adipyl-L-lysines, polyterephthalamides andpoly-(terephthaloyl-L-lysines)), poly-.epsilon.-caprolactam,polydimethylsiloxane, polyesters, poly (ethylene-vinyl acetate),polyglycolic acid, polyactic acid and its copolymers, polyglutamic acid,polylysine, polystyrene, shellac, xanthan gum, anionic polymers ofmethacrylic acid and methacrylic acid esters, hydroxyalkylcelluloses andmixtures thereof.
 130. The method of claim 129 wherein saidhydroxyalkylcellulose is hydroxypropylmethylcellulose.
 131. The methodof claim 96 wherein said texture modifier is selected from the groupconsisting of acacia gum, acrylic acid polymers and copolymers(polyacrylamides, polyacryldextrans, polyalkyl cyanoacrylates,polymethyl methacrylates), agar-agar, agarose, albumin, alginic acid andalginates, carboxyvinyl polymers, cellulose derivatives such ascellulose acetate, polyamides (nylon 6-10, poly(adipyl-L-lysines,polyterephthalamides and poly-(terephthaloyl-L-lysines)),poly-.epsilon.-caprolactam, polydimethylsiloxane, polyesters, poly(ethylene-vinyl acetate), polyglycolic acid, polyactic acid and itscopolymers, polyglutamic acid, polylysine, polystyrene, shellac, xanthangum, anionic polymers of methacrylic acid and methacrylic acid esters,hydroxyalkylcelluloses and mixtures thereof.
 132. The method of claim116 wherein said particulates have a mean rugosity of from about 1.0 toabout 1.5.
 133. The drug formulation of claim 77 wherein said chipresistant coating comprises a material selected from the groupconsisting of acacia gum, alginic acid and alginates,carboxymethylcellulose, ethylcellulose, gelatine,hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose,xanthan gum, pectin, tragacanth, microcrystalline cellulose,hydroxyethylcellulose, ethylhydroxyethylcellulose, sodiumcarboxymethylcellulose, polyethylene glycols, polyvinylpyrrolidone,polyvinyl alcohol, polyacrylic acid, gum arabic, lactose, starch (wheat,maize, potato and rice starch), sucrose, glucose, mannitol, sorbitol,xylitol, stearic acid, hydrogenated cottonseed oil, hydrogenated castoroil, vinylpyrrolidone-vinyl acetate copolymers, fructose,methylhydroxyethylcellulose, agar-agar, carrageenan, karaya gum,chitosan, starch hydrolysates and mixtures thereof.
 134. The method ofclaim 108 wherein said pliable coating comprises a plasticizer selectedfrom the group consisting of dibutyl sebacate, diethyl phthalate,triethyl citrate, tibutyl citrate, triacetin and mixtures thereof. 135.A method of preparing a multiparticulate drug formulation forgastrointestinal deposition with minimal potential for surface watercoalesence comprising preparing a non-compressed free flowing pluralityof particles comprising a core comprising a drug and a pharmaceuticallyacceptable excipient, and overcoating said core with a coating minimizeswater coalesence on the surface of said particles.
 136. A method ofpreparing a multiparticulate drug formulation for gastrointestinaldeposition with minimal static charge comprising preparing anon-compressed free flowing plurality of particles comprising a corecomprising a drug and a pharmaceutically acceptable excipient, andovercoating said core with a coating which minimizes static chargebetween said particles.
 137. A method of preparing a multiparticulatedrug formulation for gastrointestinal deposition comprising preparing anon-compressed free flowing plurality of particles comprising a corecomprising a drug and a pharmaceutically acceptable excipient air jetsieving said particles to separate said cores from fine particles; andovercoating said core with a functional coating.
 138. A method ofpreparing a multiparticulate drug formulation with improved weightuniformity for gastrointestinal deposition comprising preparing anon-compressed free flowing plurality of particles comprising a corecomprising a drug and a pharmaceutically acceptable excipient; andovercoating said core with a functional coating.
 139. A method ofpreparing a multiparticulate drug formulation for gastrointestinaldeposition with minimal change in cohesiveness in response to humiditychange comprising preparing a non-compressed free flowing plurality ofparticles comprising a core comprising a drug and a pharmaceuticallyacceptable excipient; and overcoating said core with a functionalcoating such that the cohesiveness of said particles does notsubstantially change over a humidity gradient from about 10% relativehumidity to about 90% relative humidity.
 140. The method of claim 137wherein said fine particles are less than about 50 micrometers.
 141. Themethod of claim 137 wherein said fine particles are less than about 25micrometers.
 142. The method of claim 137 wherein said fine particlesare less than about 10 micrometers.
 143. The method of claim 137 furthercomprising filtering said particles prior to air jet sieving to removeparticles greater than about 500 micrometers.
 144. The method of claim143 further comprising filtering said particles prior to air jet sievingto remove particles greater than about 750 micrometers.
 145. The methodof claim 144 further comprising filtering said particles prior to airjet sieving to remove particles greater than about 1 mm.
 146. The methodof claim 135 comprising preparing said particles with an amount ofcoloring agents which minimizes weakening of the adhesion of theovercoat to the core.
 147. The method of claim 146 wherein said coloringagent is selected from the group consisting of a lake, an opacifier or acombination thereof.
 148. The method of claim 146 wherein said coloringagent does not comprise a lake.
 149. The method of claim 146 whereinsaid coloring agent does not comprise an opacifier.
 150. The method ofclaim 146 wherein said coloring agent does not comprise a lake or anopacifier.
 151. The method of claim 135 wherein said overcoat comprisesa plasticizer.
 152. The method of claim 139 wherein the cohesiveness ofsaid particles does not substantially change over a humidity gradientfrom about 20% relative humidity to about 80% relative humidity. 153.The method of claim 152 wherein the cohesiveness of said particles doesnot substantially change over a humidity gradient from about 40%relative humidity to about 60% relative humidity.
 154. The method ofclaim 137 wherein said overcoat comprises a conductive polymer.
 155. Themethod of claim 135 wherein said drug particles having a mean diameterof greater than 10 μm to about 1 mm.
 156. The method of claim 155wherein said drug particles having a mean diameter of greater than 50 μmto about 500 μm.
 157. The method of claim 135 wherein said particlescomprise at least about 40%, at least about 50%, at least about 60%, atleast about 70% or at least about 80% drug.
 158. The method of claim 135wherein said core comprises drug coated with said excipient and saidfunctional coat overcoats the excipient coat.
 159. The method of claim135 wherein said core comprises a drug interdispersed in said excipient.160. The method of claim 159 wherein said drug and said excipient arewet granulated.
 161. The method of claim 159 wherein said drug and saidexcipient are melt granulated.
 162. The method of claim 159 wherein saiddrug and a first portion of said excipient are wet granulated and theresultant wet granulated particles are melt granulated with a secondportion of said excipient.
 163. The method of claim 162 wherein saidfirst portion of excipient and said second portion of excipient comprisethe same material.
 164. The method of claim 162 wherein said firstportion of excipient and said second portion of excipient comprisedifferent materials.
 165. The method of claim 135 wherein saidfunctional coated particles are melt granulated with a pharmaceuticallyacceptable excipient.
 166. The method of claim 161 wherein a differencebetween a film forming temperature of the melt granulating excipient anda film forming temperature of the functional coat is more than 15degrees C.
 167. The method of claim 166 wherein a difference between afilm forming temperature of the melt granulating excipient and a filmforming temperature of the functional coat is more than 20 degrees C.168. The method of claim 166 wherein a difference between a film formingtemperature of a melt granulating excipient and a film formingtemperature of the functional coat is more than 25 degrees C.
 169. Themethod of claim 161 wherein the melt granulating excipient is selectedfrom the group consisting of beeswax, white wax, emulsifying wax,hydrogenated vegetable oil, cetyl alcohol, stearyl alcohol, stearicacid; esters of wax acids; propylene glycol monostearate, glycerylmonostearate; carnauba wax, glyceryl palmitostearate, glyceryl behenate,polyethylene glycol, and a combination thereof.
 170. A multiparticulateformulation obtained according to a process of claim
 135. 171. Acontrolled release formulation comprising a drug and a sufficient amountof a lacquer agent to provide a controlled release of the drug.
 172. Theformulation of claim 171 wherein said lacquer agent is selected from thegroup consisting of corn oil, cottonseed oil, menhaden oil, pine oil,peanut oil, safflower oil, sesame oil, soybean oil, linseed oil andmixtures thereof.
 173. The formulation of claim 171 wherein said lacqueragent is selected from the group consisting of fatty acids of C8-C20oils which can be saturated, unsaturated, glycerides thereof, andcombination thereof.
 174. The formulation of claim 171 wherein saidlacquer agent is selected from the group consisting of branched orpolycarboxylated oils such as linoleic acid, linolenic acid, oleic acidand combinations thereof.
 175. The formulation of claim 171 wherein saidlacquer agent is selected from the group consisting of caprylic acid,capric acid, lauric acid, myristic acid, palmitic acid, margaric acid,stearic acid, arachidic acid, behenic acid, lignoceric acid andcombinations thereof.
 176. The formulation of claim 171 wherein saidlacquer agent is at least partially interdispersed with said drug. 177.The formulation of claim 171 wherein said lacquer agent is coated ontosaid drug.
 178. The formulation of claim 171 wherein said formulation isin multiparticulate form.
 179. The formulation of claim 171 wherein saidformulation is a tablet.
 180. The formulation of claim 171 furthercomprising a channeling agent such as polyvinylpyrrolidone,polyethyleneglycols, dextrose, sucrose, mannitol, xylitol, lactose andcombinations thereof.
 181. The formulation of claim 171 furthercomprising a dispersing agent such as colloidal silicone dioxide, talc,kaolin, silicone dioxide, colloidal calcium carbonate, bentonite,Fuller's earth, magnesium aluminum silicate and mixtures thereof.
 182. Amethod of preparing a multiparticulate drug formulation forgastrointestinal deposition comprising preparing a non-compressed freeflowing plurality of particles comprising a drug and air jet sievingsaid particles to separate fine particles.
 183. The method of claim 182wherein said fine particles are less than about 50 micrometers.
 184. Themethod of claim 182 wherein said fine particles are less than about 25micrometers.
 185. The method of claim 182 wherein said fine particlesare less than about 10 micrometers.
 186. The method of claim 182 furthercomprising filtering said particles prior to air jet sieving to removeparticles greater than about 500 micrometers.
 187. The method of claim182 further comprising filtering said particles prior to air jet sievingto remove particles greater than about 750 micrometers.
 188. The methodof claim 182 further comprising filtering said particles prior to airjet sieving to remove particles greater than about 1 mm.
 189. The methodof claim 182 further comprising placing a plurality of saidmultiparticulates in a dosing device capable of metering a unit dose ofsaid formulation for oral delivery.
 190. A composition obtained from amethod of claim
 182. 191. A formulation for gastrointestinal depositioncomprising a non-compressed free flowing plurality of particlescomprising a core comprising chlorpheniramine or a salt thereof and apharmaceutically acceptable excipient, said core overcoated with afunctional coating, said particles having a mean diameter of greaterthan 10 μm to about 1 mm.